A highly conserved 76-amino acid peptide universally found in eukaryotic cells that functions as a marker for intracellular PROTEIN TRANSPORT and degradation. Ubiquitin becomes activated through a series of complicated steps and forms an isopeptide bond to lysine residues of specific proteins within the cell. These "ubiquitinated" proteins can be recognized and degraded by proteosomes or be transported to specific compartments within the cell.
A diverse class of enzymes that interact with UBIQUITIN-CONJUGATING ENZYMES and ubiquitination-specific protein substrates. Each member of this enzyme group has its own distinct specificity for a substrate and ubiquitin-conjugating enzyme. Ubiquitin-protein ligases exist as both monomeric proteins multiprotein complexes.
A family of proteins that are structurally-related to Ubiquitin. Ubiquitins and ubiquitin-like proteins participate in diverse cellular functions, such as protein degradation and HEAT-SHOCK RESPONSE, by conjugation to other proteins.
A thioester hydrolase which acts on esters formed between thiols such as DITHIOTHREITOL or GLUTATHIONE and the C-terminal glycine residue of UBIQUITIN.
The act of ligating UBIQUITINS to PROTEINS to form ubiquitin-protein ligase complexes to label proteins for transport to the PROTEASOME ENDOPEPTIDASE COMPLEX where proteolysis occurs.
A class of enzymes that form a thioester bond to UBIQUITIN with the assistance of UBIQUITIN-ACTIVATING ENZYMES. They transfer ubiquitin to the LYSINE of a substrate protein with the assistance of UBIQUITIN-PROTEIN LIGASES.
A large multisubunit complex that plays an important role in the degradation of most of the cytosolic and nuclear proteins in eukaryotic cells. It contains a 700-kDa catalytic sub-complex and two 700-kDa regulatory sub-complexes. The complex digests ubiquitinated proteins and protein activated via ornithine decarboxylase antizyme.
A family of structurally related proteins that were originally discovered for their role in cell-cycle regulation in CAENORHABDITIS ELEGANS. They play important roles in regulation of the CELL CYCLE and as components of UBIQUITIN-PROTEIN LIGASES.
An oligomer formed from the repetitive linking of the C-terminal glycine of one UBIQUITIN molecule via an isopeptide bond to a lysine residue on a second ubiquitin molecule. It is structurally distinct from UBIQUITIN C, which is a single protein containing a tandemly arrayed ubiquitin peptide sequence.
A class of enzymes that catalyze the formation of a bond between two substrate molecules, coupled with the hydrolysis of a pyrophosphate bond in ATP or a similar energy donor. (Dorland, 28th ed) EC 6.
A subset of ubiquitin protein ligases that are formed by the association of a SKP DOMAIN PROTEIN, a CULLIN DOMAIN PROTEIN and a F-BOX DOMAIN PROTEIN.
Complexes of enzymes that catalyze the covalent attachment of UBIQUITIN to other proteins by forming a peptide bond between the C-terminal GLYCINE of UBIQUITIN and the alpha-amino groups of LYSINE residues in the protein. The complexes play an important role in mediating the selective-degradation of short-lived and abnormal proteins. The complex of enzymes can be broken down into three components that involve activation of ubiquitin (UBIQUITIN-ACTIVATING ENZYMES), conjugation of ubiquitin to the ligase complex (UBIQUITIN-CONJUGATING ENZYMES), and ligation of ubiquitin to the substrate protein (UBIQUITIN-PROTEIN LIGASES).
A class of enzymes that catalyzes the ATP-dependent formation of a thioester bond between itself and UBIQUITIN. It then transfers the activated ubiquitin to one of the UBIQUITIN-PROTEIN LIGASES.
A single protein comprised of tandem repeats of the UBIQUITIN 78-amino acid sequence. It is a product of the polyubiquitin gene which contains multiple copies of the ubiquitin coding sequence. Proteolytic processing of ubiquitin C results in the formation of individual ubiquitin molecules. This protein is distinct from POLYUBIQUITIN, which is a protein formed through isopeptide linkage of multiple ubiquitin species.
A set of protein subcomplexes involved in PROTEIN SORTING of UBIQUITINATED PROTEINS into intraluminal vesicles of MULTIVESICULAR BODIES and in membrane scission during formation of intraluminal vesicles, during the final step of CYTOKINESIS, and during the budding of enveloped viruses. The ESCRT machinery is comprised of the protein products of Class E vacuolar protein sorting genes.
A family of proteins that share the F-BOX MOTIF and are involved in protein-protein interactions. They play an important role in process of protein ubiquition by associating with a variety of substrates and then associating into SCF UBIQUITIN LIGASE complexes. They are held in the ubiquitin-ligase complex via binding to SKP DOMAIN PROTEINS.
A zinc-binding domain defined by the sequence Cysteine-X2-Cysteine-X(9-39)-Cysteine-X(l-3)-His-X(2-3)-Cysteine-X2-Cysteine -X(4-48)-Cysteine-X2-Cysteine, where X is any amino acid. The RING finger motif binds two atoms of zinc, with each zinc atom ligated tetrahedrally by either four cysteines or three cysteines and a histidine. The motif also forms into a unitary structure with a central cross-brace region and is found in many proteins that are involved in protein-protein interactions. The acronym RING stands for Really Interesting New Gene.
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
Cleavage of proteins into smaller peptides or amino acids either by PROTEASES or non-enzymatically (e.g., Hydrolysis). It does not include Protein Processing, Post-Translational.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
An E3 ubiquitin ligase primarily involved in regulation of the metaphase-to-anaphase transition during MITOSIS through ubiquitination of specific CELL CYCLE PROTEINS. Enzyme activity is tightly regulated through subunits and cofactors, which modulate activation, inhibition, and substrate specificity. The anaphase-promoting complex, or APC-C, is also involved in tissue differentiation in the PLACENTA, CRYSTALLINE LENS, and SKELETAL MUSCLE, and in regulation of postmitotic NEURONAL PLASTICITY and excitability.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
Proteins covalently modified with UBIQUITINS or UBIQUITIN-LIKE PROTEINS.
A family of structurally-related proteins that were originally identified by their ability to complex with cyclin proteins (CYCLINS). They share a common domain that binds specifically to F-BOX MOTIFS. They take part in SKP CULLIN F-BOX PROTEIN LIGASES, where they can bind to a variety of F-BOX PROTEINS.
ENDOPEPTIDASES which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by CYSTEINE PROTEINASE INHIBITORS such as CYSTATINS and SULFHYDRYL REAGENTS.
Members of the peptidase C19 family which regulate signal transduction by removing UBIQUITIN from specific protein substrates via a process known as deubiquitination or deubiquitylation.
An essential amino acid. It is often added to animal feed.
Proto-oncogene proteins that negatively regulate RECEPTOR PROTEIN-TYROSINE KINASE signaling. It is a UBIQUITIN-PROTEIN LIGASE and the cellular homologue of ONCOGENE PROTEIN V-CBL.
Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.
Systems of enzymes which function sequentially by catalyzing consecutive reactions linked by common metabolic intermediates. They may involve simply a transfer of water molecules or hydrogen atoms and may be associated with large supramolecular structures such as MITOCHONDRIA or RIBOSOMES.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.
Enzymes that catalyze the cleavage of a carbon-nitrogen bond by means other than hydrolysis or oxidation. Subclasses are the AMMONIA-LYASES, the AMIDINE-LYASES, the amine-lyases, and other carbon-nitrogen lyases. EC 4.3.
Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS.
A family of F-box domain proteins that contain sequences that are homologous to the beta subunit of transducin (BETA-TRANSDUCIN). They play an important role in the protein degradation pathway by becoming components of SKP CULLIN F-BOX PROTEIN LIGASES, which selectively act on a subset of proteins including beta-catenin and IkappaBbeta.
Transport proteins that carry specific substances in the blood or across cell membranes.
Established cell cultures that have the potential to propagate indefinitely.
A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.
The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.
Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.
Compounds that inhibit the function or proteolytic action of the PROTEASOME.
A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.
Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a CONSERVED SEQUENCE which can be represented by a CONSENSUS SEQUENCE.
A 1.5-kDa small ubiquitin-related modifier protein that can covalently bind via an isopeptide link to a number of cellular proteins. It may play a role in intracellular protein transport and a number of other cellular processes.
A group of acylated oligopeptides produced by Actinomycetes that function as protease inhibitors. They have been known to inhibit to varying degrees trypsin, plasmin, KALLIKREINS, papain and the cathepsins.
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.
The ability of a protein to retain its structural conformation or its activity when subjected to physical or chemical manipulations.
Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.
The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport.
A class of structurally related proteins of 12-20 kDa in size. They covalently modify specific proteins in a manner analogous to UBIQUITIN.
Macromolecular complexes formed from the association of defined protein subunits.
Hydrolases that specifically cleave the peptide bonds found in PROTEINS and PEPTIDES. Examples of sub-subclasses for this group include EXOPEPTIDASES and ENDOPEPTIDASES.
A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.
The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.
The aggregation of soluble ANTIGENS with ANTIBODIES, alone or with antibody binding factors such as ANTI-ANTIBODIES or STAPHYLOCOCCAL PROTEIN A, into complexes large enough to fall out of solution.
Screening techniques first developed in yeast to identify genes encoding interacting proteins. Variations are used to evaluate interplay between proteins and other molecules. Two-hybrid techniques refer to analysis for protein-protein interactions, one-hybrid for DNA-protein interactions, three-hybrid interactions for RNA-protein interactions or ligand-based interactions. Reverse n-hybrid techniques refer to analysis for mutations or other small molecules that dissociate known interactions.
Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.
An E3 UBIQUITIN LIGASE that interacts with and inhibits TUMOR SUPPRESSOR PROTEIN P53. Its ability to ubiquitinate p53 is regulated by TUMOR SUPPRESSOR PROTEIN P14ARF.
Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.
A type of POST-TRANSLATIONAL PROTEIN MODIFICATION by SMALL UBIQUITIN-RELATED MODIFIER PROTEINS (also known as SUMO proteins).
Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.
Cell surface receptors for AUTOCRINE MOTILITY FACTOR, which is the secreted form of GLUCOSE-6-PHOSPHATE ISOMERASE. The receptor has an unusual composition in that it shares some structural similarities with G-PROTEIN-COUPLED RECEPTORS and functions as an ubiquitin protein ligase when internalized.
Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.
A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymes
Ligases that catalyze the joining of adjacent AMINO ACIDS by the formation of carbon-nitrogen bonds between their carboxylic acid groups and amine groups.
Protein modules with conserved ligand-binding surfaces which mediate specific interaction functions in SIGNAL TRANSDUCTION PATHWAYS and the specific BINDING SITES of their cognate protein LIGANDS.
The parts of a macromolecule that directly participate in its specific combination with another molecule.
A gene silencing phenomenon whereby specific dsRNAs (RNA, DOUBLE-STRANDED) trigger the degradation of homologous mRNA (RNA, MESSENGER). The specific dsRNAs are processed into SMALL INTERFERING RNA (siRNA) which serves as a guide for cleavage of the homologous mRNA in the RNA-INDUCED SILENCING COMPLEX. DNA METHYLATION may also be triggered during this process.
Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.
Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
Proteins which maintain the transcriptional quiescence of specific GENES or OPERONS. Classical repressor proteins are DNA-binding proteins that are normally bound to the OPERATOR REGION of an operon, or the ENHANCER SEQUENCES of a gene until a signal occurs that causes their release.
Processes involved in the formation of TERTIARY PROTEIN STRUCTURE.
A cell line derived from cultured tumor cells.
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.
Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.
Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. ENDOSOMES play a central role in endocytosis.
The arrangement of two or more amino acid or base sequences from an organism or organisms in such a way as to align areas of the sequences sharing common properties. The degree of relatedness or homology between the sequences is predicted computationally or statistically based on weights assigned to the elements aligned between the sequences. This in turn can serve as a potential indicator of the genetic relatedness between the organisms.
NMR spectroscopy on small- to medium-size biological macromolecules. This is often used for structural investigation of proteins and nucleic acids, and often involves more than one isotope.
The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).
Proteins prepared by recombinant DNA technology.
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.
CELL LINES derived from the CV-1 cell line by transformation with a replication origin defective mutant of SV40 VIRUS, which codes for wild type large T antigen (ANTIGENS, POLYOMAVIRUS TRANSFORMING). They are used for transfection and cloning. (The CV-1 cell line was derived from the kidney of an adult male African green monkey (CERCOPITHECUS AETHIOPS).)
A generic term for any circumscribed mass of foreign (e.g., lead or viruses) or metabolically inactive materials (e.g., ceroid or MALLORY BODIES), within the cytoplasm or nucleus of a cell. Inclusion bodies are in cells infected with certain filtrable viruses, observed especially in nerve, epithelial, or endothelial cells. (Stedman, 25th ed)
The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.
Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.
Exogenous and endogenous compounds which inhibit CYSTEINE ENDOPEPTIDASES.
Proteins that are normally involved in holding cellular growth in check. Deficiencies or abnormalities in these proteins may lead to unregulated cell growth and tumor development.
A ubiquitin-protein ligase that mediates OXYGEN-dependent polyubiquitination of HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT. It is inactivated in VON HIPPEL-LINDAU SYNDROME.
Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.
A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.
Proteins produced from GENES that have acquired MUTATIONS.
Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.
The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)
A system of cisternae in the CYTOPLASM of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (CELL MEMBRANE) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced (ENDOPLASMIC RETICULUM, ROUGH); otherwise it is said to be smooth-surfaced (ENDOPLASMIC RETICULUM, SMOOTH). (King & Stansfield, A Dictionary of Genetics, 4th ed)
Immature ERYTHROCYTES. In humans, these are ERYTHROID CELLS that have just undergone extrusion of their CELL NUCLEUS. They still contain some organelles that gradually decrease in number as the cells mature. RIBOSOMES are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic "reticulum" (not the same as the ENDOPLASMIC RETICULUM), hence the name reticulocytes.
Methods for determining interaction between PROTEINS.
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
Cytoplasmic vesicles formed when COATED VESICLES shed their CLATHRIN coat. Endosomes internalize macromolecules bound by receptors on the cell surface.
Motifs in DNA- and RNA-binding proteins whose amino acids are folded into a single structural unit around a zinc atom. In the classic zinc finger, one zinc atom is bound to two cysteines and two histidines. In between the cysteines and histidines are 12 residues which form a DNA binding fingertip. By variations in the composition of the sequences in the fingertip and the number and spacing of tandem repeats of the motif, zinc fingers can form a large number of different sequence specific binding sites.
Proteins found in any species of fungus.
A species of CERCOPITHECUS containing three subspecies: C. tantalus, C. pygerythrus, and C. sabeus. They are found in the forests and savannah of Africa. The African green monkey (C. pygerythrus) is the natural host of SIMIAN IMMUNODEFICIENCY VIRUS and is used in AIDS research.
Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured. Such rupture is supposed to be under metabolic (hormonal) control. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)
A group of enzymes which catalyze the hydrolysis of ATP. The hydrolysis reaction is usually coupled with another function such as transporting Ca(2+) across a membrane. These enzymes may be dependent on Ca(2+), Mg(2+), anions, H+, or DNA.
Proteins that originate from plants species belonging to the genus ARABIDOPSIS. The most intensely studied species of Arabidopsis, Arabidopsis thaliana, is commonly used in laboratory experiments.
Protein structural motifs that play a role in protein-protein binding. The motifs are comprised of approximately 50 residues. Their name derives from the fact that they were found in cyclin F.
Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation.
A degradation process whereby incorrectly folded proteins are selectively transported out of the ENDOPLASMIC RETICULUM and into the CYTOSOL. The misfolded proteins are subsequently ubiquitinated and degraded by the PROTEASOME.
The artificial induction of GENE SILENCING by the use of RNA INTERFERENCE to reduce the expression of a specific gene. It includes the use of DOUBLE-STRANDED RNA, such as SMALL INTERFERING RNA and RNA containing HAIRPIN LOOP SEQUENCE, and ANTI-SENSE OLIGONUCLEOTIDES.
A group of cell cycle proteins that negatively regulate the activity of CYCLIN/CYCLIN-DEPENDENT KINASE complexes. They inhibit CELL CYCLE progression and help control CELL PROLIFERATION following GENOTOXIC STRESS as well as during CELL DIFFERENTIATION.
Endosomes containing intraluminal vesicles which are formed by the inward budding of the endosome membrane. Multivesicular bodies (MVBs) may fuse with other organelles such as LYSOSOMES or fuse back with the PLASMA MEMBRANE releasing their contents by EXOCYTOSIS. The MVB intraluminal vesicles released into the extracellular environment are known as EXOSOMES.
Highly conserved proteins that specifically bind to and activate the anaphase-promoting complex-cyclosome, promoting ubiquitination and proteolysis of cell-cycle-regulatory proteins. Cdc20 is essential for anaphase-promoting complex activity, initiation of anaphase, and cyclin proteolysis during mitosis.
Together with the Apc2 subunit, forms the catalytic core of the E3 ubiquitin ligase, anaphase-promoting complex-cyclosome. It has a RING H2 domain which interacts with the cullin domain of Apc2. Apc11 also interacts with the E2 ubiquitin ligases involved in APC-C ubiquitination reactions.
The protein constituents of muscle, the major ones being ACTINS and MYOSINS. More than a dozen accessory proteins exist including TROPONIN; TROPOMYOSIN; and DYSTROPHIN.
Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each.
A plant genus of the family BRASSICACEAE that contains ARABIDOPSIS PROTEINS and MADS DOMAIN PROTEINS. The species A. thaliana is used for experiments in classical plant genetics as well as molecular genetic studies in plant physiology, biochemistry, and development.
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.
Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.
A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a CONSENSUS SEQUENCE. AMINO ACID MOTIFS are often composed of conserved sequences.
Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS.
The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.
The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.
Single chains of amino acids that are the units of multimeric PROTEINS. Multimeric proteins can be composed of identical or non-identical subunits. One or more monomeric subunits may compose a protomer which itself is a subunit structure of a larger assembly.
A signal transducing tumor necrosis factor receptor associated factor that is involved in regulation of NF-KAPPA B signalling and activation of JNK MITOGEN-ACTIVATED PROTEIN KINASES.
Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.
One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
A type of CELL NUCLEUS division by means of which the two daughter nuclei normally receive identical complements of the number of CHROMOSOMES of the somatic cells of the species.
The process of cleaving a chemical compound by the addition of a molecule of water.
Nuclear antigen with a role in DNA synthesis, DNA repair, and cell cycle progression. PCNA is required for the coordinated synthesis of both leading and lagging strands at the replication fork during DNA replication. PCNA expression correlates with the proliferation activity of several malignant and non-malignant cell types.
Proteins that originate from insect species belonging to the genus DROSOPHILA. The proteins from the most intensely studied species of Drosophila, DROSOPHILA MELANOGASTER, are the subject of much interest in the area of MORPHOGENESIS and development.
The level of protein structure in which regular hydrogen-bond interactions within contiguous stretches of polypeptide chain give rise to alpha helices, beta strands (which align to form beta sheets) or other types of coils. This is the first folding level of protein conformation.
The facilitation of a chemical reaction by material (catalyst) that is not consumed by the reaction.
The segregation and degradation of damaged or unwanted cytoplasmic constituents by autophagic vacuoles (cytolysosomes) composed of LYSOSOMES containing cellular components in the process of digestion; it plays an important role in BIOLOGICAL METAMORPHOSIS of amphibians, in the removal of bone by osteoclasts, and in the degradation of normal cell components in nutritional deficiency states.
An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers.
A cyclin-dependent kinase inhibitor that coordinates the activation of CYCLIN and CYCLIN-DEPENDENT KINASES during the CELL CYCLE. It interacts with active CYCLIN D complexed to CYCLIN-DEPENDENT KINASE 4 in proliferating cells, while in arrested cells it binds and inhibits CYCLIN E complexed to CYCLIN-DEPENDENT KINASE 2.
The rate dynamics in chemical or physical systems.
Protein analogs and derivatives of the Aequorea victoria green fluorescent protein that emit light (FLUORESCENCE) when excited with ULTRAVIOLET RAYS. They are used in REPORTER GENES in doing GENETIC TECHNIQUES. Numerous mutants have been made to emit other colors or be sensitive to pH.
A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are SACCHAROMYCES CEREVISIAE; therapeutic dried yeast is YEAST, DRIED.
The phosphoprotein encoded by the BRCA1 gene (GENE, BRCA1). In normal cells the BRCA1 protein is localized in the nucleus, whereas in the majority of breast cancer cell lines and in malignant pleural effusions from breast cancer patients, it is localized mainly in the cytoplasm. (Science 1995;270(5237):713,789-91)
A syndrome characterized by multiple abnormalities, MENTAL RETARDATION, and movement disorders. Present usually are skull and other abnormalities, frequent infantile spasms (SPASMS, INFANTILE); easily provoked and prolonged paroxysms of laughter (hence "happy"); jerky puppetlike movements (hence "puppet"); continuous tongue protrusion; motor retardation; ATAXIA; MUSCLE HYPOTONIA; and a peculiar facies. It is associated with maternal deletions of chromosome 15q11-13 and other genetic abnormalities. (From Am J Med Genet 1998 Dec 4;80(4):385-90; Hum Mol Genet 1999 Jan;8(1):129-35)
Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA.
A subunit of the anaphase-promoting complex whose primary function is to provide structural support for the catalytic and substrate-recognition modules of the complex. Apc5, along with Apc4, tethers the tetratricopeptide-coactivator binding subcomplex to the main structural subunit, Apc1.
The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.
Microscopy of specimens stained with fluorescent dye (usually fluorescein isothiocyanate) or of naturally fluorescent materials, which emit light when exposed to ultraviolet or blue light. Immunofluorescence microscopy utilizes antibodies that are labeled with fluorescent dye.
A broad category of proteins involved in the formation, transport and dissolution of TRANSPORT VESICLES. They play a role in the intracellular transport of molecules contained within membrane vesicles. Vesicular transport proteins are distinguished from MEMBRANE TRANSPORT PROTEINS, which move molecules across membranes, by the mode in which the molecules are transported.
The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.
Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).
The assembly of the QUATERNARY PROTEIN STRUCTURE of multimeric proteins (MULTIPROTEIN COMPLEXES) from their composite PROTEIN SUBUNITS.
A protein serine-threonine kinase that catalyzes the PHOSPHORYLATION of I KAPPA B PROTEINS. This enzyme also activates the transcription factor NF-KAPPA B and is composed of alpha and beta catalytic subunits, which are protein kinases and gamma, a regulatory subunit.
Proteins that are coded by immediate-early genes, in the absence of de novo protein synthesis. The term was originally used exclusively for viral regulatory proteins that were synthesized just after viral integration into the host cell. It is also used to describe cellular proteins which are synthesized immediately after the resting cell is stimulated by extracellular signals.
The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990)
A transferase that catalyzes the addition of aliphatic, aromatic, or heterocyclic FREE RADICALS as well as EPOXIDES and arene oxides to GLUTATHIONE. Addition takes place at the SULFUR. It also catalyzes the reduction of polyol nitrate by glutathione to polyol and nitrite.

RPN4 is a ligand, substrate, and transcriptional regulator of the 26S proteasome: a negative feedback circuit. (1/5483)

The RPN4 (SON1, UFD5) protein of the yeast Saccharomyces cerevisiae is required for normal levels of intracellular proteolysis. RPN4 is a transcriptional activator of genes encoding proteasomal subunits. Here we show that RPN4 is required for normal levels of these subunits. Further, we demonstrate that RPN4 is extremely short-lived (t(1/2) approximately 2 min), that it directly interacts with RPN2, a subunit of the 26S proteasome, and that rpn4Delta cells are perturbed in their cell cycle. The degradation signal of RPN4 was mapped to its N-terminal region, outside the transcription-activation domains of RPN4. The ability of RPN4 to augment the synthesis of proteasomal subunits while being metabolically unstable yields a negative feedback circuit in which the same protein up-regulates the proteasome production and is destroyed by the assembled active proteasome.  (+info)

Raft-partitioning of the ubiquitin ligases Cbl and Nedd4 upon IgE-triggered cell signaling. (2/5483)

The high affinity receptor for IgE, FcepsilonRI on mast cells and basophils plays an essential role in immunological defense. Upon multivalent antigen binding, FcepsilonRI becomes phoshorylated by the protein-tyrosine kinase Lyn, as a result of receptor clustering in lipid rafts. FcepsilonRI has been shown to be ubiquitinated. Ubiquitination can lead to degradation by proteasomes, but it can also act as a sorting signal to internalize proteins destined to the endosomal/lysosomal pathway. We have analyzed whether FcepsilonRI ubiquitination takes place within rafts. We report biochemical and imaging evidence in rat basoleukemia cells for the presence of ubiquitinated FcepsilonRI in clustered rafts upon receptor activation. Moreover, we demonstrated that the ubiquitin ligases Cbl and Nedd4 colocalize with FcepsilonRI patches and showed that both ligases become associated with lipid rafts after activation of IgE signaling. Because Cbl is known to interact with the FcepsilonRI signaling complex, ubiquitination is likely to be an important parameter regulating IgE-triggered signaling occurring in rafts.  (+info)

The Mdm-2 amino terminus is required for Mdm2 binding and SUMO-1 conjugation by the E2 SUMO-1 conjugating enzyme Ubc9. (3/5483)

Covalent attachment of SUMO-1 to Mdm2 requires the activation of a heterodimeric Aos1-Uba2 enzyme (ubiquitin-activating enzyme (E1)) followed by the conjugation of Sumo-1 to Mdm2 by Ubc9, a protein with a strong sequence similarity to ubiquitin carrier proteins (E2s). Upon Sumo-1 conjugation, Mdm2 is protected from self-ubiquitination and elicits greater ubiquitin-protein isopeptide ligase (E3) activity toward p53, thereby increasing its oncogenic potential. Because of the biological implication of Mdm2 sumoylation, we mapped Ubc9 binding on Mdm2. Here we demonstrate that Ubc9 can associate with Mdm2 only if amino acids 40-59 within the N terminus of Mdm2 are present. Mdm2 from which amino acids 40-59 have been deleted can no longer be sumoylated. Furthermore, addition of a peptide that corresponds to amino acids 40-59 on Mdm2 to a sumoylation reaction efficiently inhibits Mdm2 sumoylation in vitro and in vivo. In UV-treated cells Mdm2 exhibits reduced association with Ubc9, which coincides with decreased Mdm2 sumoylation. Our findings regarding the association of Ubc9 with Mdm2, and the effect of UV-irradiation on Ubc9 binding, point to an additional level in the regulation of Mdm2 sumoylation under normal growth conditions as well as in response to stress conditions.  (+info)

Heat capacity changes upon burial of polar and nonpolar groups in proteins. (4/5483)

In this paper we address the question of whether the burial of polar and nonpolar groups in the protein locale is indeed accompanied by the heat capacity changes, DeltaC(p), that have an opposite sign, negative for nonpolar groups and positive for polar groups. To accomplish this, we introduced amino acid substitutions at four fully buried positions of the ubiquitin molecule (Val5, Val17, Leu67, and Gln41). We substituted Val at positions 5 and 17 and Leu at position 67 with a polar residue, Asn. As a control, Ala was introduced at the same three positions. We also replaced the buried polar Gln41 with Val and Leu, nonpolar residues that have similar size and shape as Gln. As a control, Asn was introduced at Gln41 as well. The effects of these amino acid substitutions on the stability, and in particular, on the heat capacity change upon unfolding were measured using differential scanning calorimetry. The effect of the amino acid substitutions on the structure was also evaluated by comparing the (1)H-(15)N HSQC spectra of the ubiquitin variants. It was found that the Ala substitutions did not have a considerable effect on the heat capacity change upon unfolding. However, the substitutions of aliphatic side chains (Val or Leu) with a polar residue (Asn) lead to a significant (> 30%) decrease in the heat capacity change upon unfolding. The decrease in heat capacity changes does not appear to be the result of significant structural perturbations as seen from the HSQC spectra of the variants. The substitution of a buried polar residue (Gln41) to a nonpolar residue (Leu or Val) leads to a significant (> 25%) increase in heat capacity change upon unfolding. These results indicate that indeed the heat capacity change of burial of polar and nonpolar groups has an opposite sign. However, the observed changes in DeltaC(p) are several times larger than those predicted, based on the changes in water accessible surface area upon substitution.  (+info)

Proteasomes are involved in the constitutive degradation of growth hormone receptors. (5/5483)

In the mouse Ba/F3-hGHR cell line, which stably expresses human growth hormone receptors (hGHRs), the hGHRs were rapidly degraded in the absence of the ligand. Human growth hormone-binding protein (hGH-BP), a soluble form of hGHR, was released from Ba/F3-hGHR cells, but the hGH-BP release was less than 1% of total hGHRs in the cells. Therefore, the hGH-BP release does not markedly contribute to hGHR degradation in Ba/F3-hGHR cells. The constitutive degradation of hGHRs was inhibited by the proteasome inhibitors MG-132 and clasto-lactacystin beta-lactone, or the vacuolar H+-ATPase inhibitor, bafilomycin A1. hGH-enhanced degradation of hGHRs was also inhibited by MG-132. Moreover, MG-132 inhibited the internalization of hGHRs as assessed by 125I-hGH binding to the cell surfaces. Ubiquitinated hGHRs were detected in the cell lysate and increased by hGH-treatment. Furthermore, MG-132 accumulated the ubiquitinated hGHRs induced by hGH. However, the ratio of ubiquitinated hGHRs to unubiquitinated hGHRs was very small, even with treatment involving both hGH and MG-132. In the hGH-untreated cells, the ubiquitinated hGHRs were weakly detected. However, the ubiquitination of hGHR was not enhanced by MG-132 as a result of immunoblotting. Thus, the ubiquitination of hGHR is unlikely to be involved, at least in the constitutive degradation. Taken together, both the proteasome pathway and endosome/lysosome pathway are involved in the constitutive degradation of hGHRs. Our results also suggest that ubiquitination of the hGHR itself is unlikely to be the trigger of the proteasome-dependent degradation.  (+info)

High and sustained transgene expression in vivo from plasmid vectors containing a hybrid ubiquitin promoter. (6/5483)

Sustained transgene expression will be required for the successful treatment of most genetic diseases being considered for gene therapy. The initially high levels of expression attained with plasmid DNA (pDNA) vectors containing viral promoters, such as that from cytomegalovirus (CMV), decline precipitously to near-background levels within two to three weeks. Here we constructed pDNA vectors containing the human cellular UBB (encoding ubiquitin B; Ub) promoter and evaluated their expression in the mouse lung. Cationic lipid-pDNA complexes were instilled intranasally (IN) or injected intravenously (IV) into immunodeficient BALB/c mice. Chloramphenicol acetyltransferase (CAT) reporter gene expression from the UBB promoter was initially very low at day 2 post-administration, but by day 35 exceeded the level of expression attained from a CMV promoter vector by four- to ninefold. Appending a portion of the CMV enhancer 5' of the UBB promoter (CMV-Ub) increased CAT expression to nearly that of the CMV promoter and expression persisted in the lung for at least 3 months, with 50% of day 2 levels remaining at day 84. In the liver, expression from the CMV-Ub hybrid promoter was sustained for 42 days. As previous studies have shown that eliminating immunostimulatory CpG motifs in pDNA vectors reduces their toxicity, we constructed a CpG-deficient version of the CMV-Ub vector expressing alpha-galactosidase A, the enzyme deficient in Fabry disease, a lysosomal storage disorder. After IN or IV administration, levels of alpha-galactosidase A from this vector were not only undiminished but increased 500% to 1500% by day 35. Our results indicate that CpG-reduced plasmid vectors containing a CMV-Ub hybrid promoter may provide the long-term expression required for a practical gene therapeutic.  (+info)

Effects of arachidonic and docosahexaenoic acids on secretion and degradation of bile salt-dependent lipase in AR4-2J cells. (7/5483)

In this study we demonstrated that two polyunsaturated fatty acids, arachidonic acid (AA, n-6) and docosahexaenoic acid (DHA, n-3), modulate the secretion of bile salt-dependent lipase (BSDL) by pancreatic AR4-2J cells. The effects of AA and DHA were also compared with that of the monounsaturated fatty acid, oleic acid (OA). Our results showed that the chronic treatment of cells with AA or DHA, that did not affect the biosynthesis rate of BSDL, similarly decreased the amount of secreted BSDL and perturbed the intracellular partitioning of the enzyme, whereas OA had no effect. Particularly, AA and DHA induced the retention of the enzyme in microsomes and lowered its content in the cell cytosol. We have further shown that AA treatment decreased the ubiquitination of the protein, and consequently diminished its export toward the cytosol, a result that might explain the retention of BSDL in microsomes and correlated with membrane phospholipids alteration. The retained protein was further degraded by a nonproteasomal pathway that likely involves ATP-dependent endoplasmic reticulum proteases. These findings concerning the regulation of the pancreatic BSDL secretion by two polyunsaturated acids, AA and DHA, might be of physiological importance in the plasmatic and cellular cholesterol homeostasis.  (+info)

Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor NF-kappa B. (8/5483)

Control of microbial infection requires regulated induction of NF-kappaB-dependent proinflammatory cytokines such as IL-12 and TNF-alpha. Activation of this important transcription factor is driven by phosphorylation-dependent degradation of the inhibitory IkappaB molecule, an event which enables NF-kappaB translocation from the cytoplasm to the nucleus. In this study, we show that intracellular infection of macrophages with the protozoan parasite Toxoplasma gondii induces rapid IkappaB phosphorylation and degradation. Nevertheless, NF-kappaB failed to translocate to the nucleus, enabling the parasite to invade cells without triggering proinflammatory cytokine induction. Infected cells subsequently subjected to LPS triggering were severely crippled in IL-12 and TNF-alpha production, a result of tachyzoite-induced blockade of NF-kappaB nuclear translocation. Our results are the first to demonstrate the ability of an intracellular protozoan to actively interfere with the NF-kappaB activation pathway in macrophages, an activity that may enable parasite survival within the host.  (+info)

The covalent attachment of ubiquitin to substrate proteins (ubiquitylation) is a post-translational modification that has major roles in regulating protein turnover and cell signalling. An E1-E2-E3 enzyme cascade tightly controls this process, but the nature of ubiquitin modification is highly variable. Single ubiquitin moieties or polyubiquitin chains of eight different linkages can be attached to proteins. The E2 ubiquitin conjugating enzymes and E3 ubiquitin ligases have critical roles in determining both the substrate and the type of ubiquitin modification. A large family of E3 ubiquitin ligases that contain both substrate recruitment and RING domains confer specificity within the ubiquitylation cascade. To activate ubiquitin transfer, RING domains bind an E2~ubiquitin conjugate and stabilise the ubiquitin moiety in a defined conformation that primes the active site on the E2 for nucleophilic attack. However, from the few examples that have been characterised, it is already clear that ...
Ubiquitin regulates a myriad of important cellular processes through covalent attachment to its substrates. A classic role for ubiquitin is to flag proteins for destruction by the proteasome. Recent studies indicate that ubiquitin-binding proteins (e.g. Rad23, Dsk2, Rpn10) play a pivotal role in transferring ubiquitylated proteins to the proteasome. However, the specific role of these ubiquitin receptors remains poorly defined. A key to unraveling the functions of these ubiquitin receptors is to identify their cellular substrates and biological circuits they are involved in. Although many strategies have been developed for substrate isolation, the identification of physiological targets of proteolytic pathways has proven to be quite challenging. Using a genome-wide functional screen, we have identified 11 yeast genes that cause slower growth upon their overexpression in cells lacking two ubiquitin-binding proteins Rad23 and Dsk2. Our results suggest that proper functioning of Rad23 and Dsk2 is required
ATP dependent protein degradation in reticulocyte lysate requires ubiquitin, a highly conserved heat stable protein. In the presence of ATP, ubiquitin is found to form alkaline-stable covalent conjugates with protein substrates. Ubiquitin conjugates are thought to play a critical role in protein degradation. It was first proposed that the covalent attachment of ubiquitin targets protein substrates for proteolytic degradation. However, more recent evidence suggests an alternative model where ubiquitin derepresses a protease by inactivating its endogenous inhibitor.;Ubiquitin conjugation requires activation of ubiquitin to a high energy intermediate by ubiquitin activating enzyme. It has been postulated that activated ubiquitin is then transferred to lysine residues of protein substrates through the action of ubiquitin conjugating enzyme or ubiquitin peptidyl transferase.;We isolated ubiquitin peptidyl transferases from human erythrocytes. Four fractions of ubiquitin peptidyl transferase activity ...
TY - JOUR. T1 - Mechanism-based proteomics tools based on ubiquitin and ubiquitin-like proteins. T2 - Synthesis of active site-directed probes. AU - Ovaa, Huib. AU - Galardy, Paul J.. AU - Ploegh, Hidde L.. PY - 2005. Y1 - 2005. N2 - The families of ubiquitin and ubiquitin-like modifiers are involved in the regulation of many biochemical pathways. The steady-state level of polypeptide modification with these molecules depends on the opposing activity of conjugating and deconjugating enzymes. Here we describe the generation of mechanism-dependent active site-directed probes that target the large family of ubiquitin/ubiquitin-like isopeptidases. To maintain substrate specificity for these enzymes, we have based the development of these probes on full-length sequences of ubiquitin and several ubiquitin-like molecules. For their construction, this approach necessitates the use of a combination of organic synthesis and expressed protein ligation. These probes have been used in the isolation and ...
Linear ubiquitin chains are important regulators of cellular signalling pathways that control innate immunity and inflammation through nuclear factor (NF)-κB activation and protection against tumour necrosis factor-α-induced apoptosis. They are synthesized by HOIP, which belongs to the RBR (RING-bet …
ubiquitin a peptide 76 amino acids in length that can be covalently attached to target lysines either as a monomer or as a lysine-linked polymer. Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains. Only the 76 amino acids of monoubiquitin product are shown in this entry. At the protein level, it is not possible to determine which of the four genes a given ubiquitin chain was derived from. Hundreds of ubiquitin ligases and hydrolases have been identified, implicating ubiquitin as a major regulatory element in many crucial cellular systems. It can be covalently bound to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer ...
We have probed the interactions between HOIP and NEMO by solving a cocrystal structure of NZF1 of human HOIP and CoZi of mouse NEMO, while our mutational studies have been performed using mouse HOIP. However, the surface residues from HOIP that interact with NEMO are fully conserved in human and mouse species (Fig. 3J). Our mutational analyses based on the structure of the cocrystal show that direct recognition of NEMO by HOIP plays a major role in NF-κB activation following conjugation of linear chains to NEMO. Although the RING-IBR-RING region of HOIP is the catalytic center for linear polyubiquitination by LUBAC (7), recent results obtained using an in vitro ubiquitin assay have suggested that the RING2 domain of HOIL-1L plays a role in linear polyubiquitination of NEMO (38). However, given that the HOIP-SHARPIN complex effectively linearly polyubiquitinates NEMO in vitro and activates NF-κB in cells (12), any involvement of the RING2 domain of HOIL-1L in linear polyubiquitination of NEMO ...
TY - JOUR. T1 - Vps9p CUE domain ubiquitin binding is required for efficient endocytic protein traffic. AU - Davies, Brian A.. AU - Topp, Justin D.. AU - Sfeir, Agnel J.. AU - Katzmann, David J.. AU - Carney, Darren S.. AU - Tall, Gregory G.. AU - Friedberg, Andrew S.. AU - Deng, Li. AU - Chen, Zhijian. AU - Horazdovsky, Bruce F.. PY - 2003/5/30. Y1 - 2003/5/30. N2 - Rab5 GTPases are key regulators of protein trafficking through the early stages of the endocytic pathway. The yeast Rab5 ortholog Vps21p is activated by its guanine nucleotide exchange factor Vps9p. Here we show that Vps9p binds ubiquitin and that the CUE domain is necessary and sufficient for this interaction. Vps9p ubiquitin binding is required for efficient endocytosis of Ste3p but not for the delivery of the biosynthetic cargo carboxypeptidase Y to the vacuole. In addition, Vps9p is itself monoubiquitylated. Ubiquitylation is dependent on a functional CUE domain and Rsp5p, an E3 ligase that participates in cell surface receptor ...
TY - JOUR. T1 - Hect E3 ubiquitin ligase Tom1 controls Dia2 degradation during the cell cycle. AU - Kim, Dong Hwan. AU - Koepp, Deanna M.. PY - 2012/11/1. Y1 - 2012/11/1. N2 - The ubiquitin proteasome system plays a pivotal role in controlling the cell cycle. The budding yeast F-box protein Dia2 is required for genomic stability and is targeted for ubiquitin-dependent degradation in a cell cycle-dependent manner, but the identity of the ubiquitination pathway is unknown. We demonstrate that the Hect domain E3 ubiquitin ligase Tom1 is required for Dia2 protein degradation. Deletion of DIA2 partially suppresses the temperature-sensitive phenotype of tom1 mutants. Tom1 is required for Dia2 ubiquitination and degradation during G1 and G2/M phases of the cell cycle, whereas the Dia2 protein is stabilized during S phase. We find that Tom1 binding to Dia2 is enhanced in G1 and reduced in S phase, suggesting a mechanism for this proteolytic switch. Tom1 recognizes specific, positively charged residues ...
Eukaryotes contain a highly conserved multienzyme system which covalently links a small protein, ubiquitin, to a variety of intracellular proteins that bear degradation signals recognized by this system. The resulting ubiquitin-protein conjugates are degraded by the 26S proteasome, an ATP-dependent protease. Pathways that involve ubiquitin play major roles in a huge variety of processes, including cell differentiation, cell cycle, and responses to stress. In this article we briefly review the design of the ubiquitin system, and describe two recent advances, the finding that ubiquitin ligases interact with specific components of the 26S proteasome, and the demonstration that peptides accelerate their uptake into cells by activating the N-end rule pathway, one of several proteolytic pathways of the ubiquitin system.. ...
Our work has revealed a partial molecular understanding for how BRCA1 recognizes DNA damage and competes with opposing DNA repair proteins to control genome integrity. We have demonstrated that an interaction between the BRCA1 BRCT domain and the RAP80 ubiquitin binding protein targets BRCA1 to K63-linked ubiquitin structures present at DNA damage sites. The RAP80 ubiquitin interaction motifs (UIMs) provide an ubiquitin recognition element to target the BRCA1 E3 ligase and a K63-ubiquitin specific deubiquitinating enzyme BRCC36 to DNA double strand breaks. Each of these activities is required for appropriate DNA damage checkpoint and repair responses (Sobhian et al. Science 2007; Shao et al. Genes&Dev 2009; Tang et al. Nat Struct & Mol Biol 2013; Jiang et al. Genes Dev 2015; Zeqiraj et al. Mol Cell 2015). Cancer causing BRCA1 BRCT mutants fail to interact with RAP80 and consequently demonstrate inefficient recruitment to DNA damage sites. Moreover, germline mutations in RAP80 and Abraxas are ...
MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses.MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses. ...
The ubiquitin binding zinc finger (UBZ) domain in the C-terminal portion of Polη has been found to interact with ubiquitin. However, the affinity between the Polη UBZ and ubiquitin was shown to be low with a previously reported Kd of 73-81 μM. This low-affinity binding between Polη UBZ and ubiquitin has been
TY - JOUR. T1 - Ubiquilin interacts with ubiquitylated proteins and proteasome through its ubiquitin-associated and ubiquitin-like domains. AU - Ko, Han Seok. AU - Uehara, Takashi. AU - Tsuruma, Kazuhiro. AU - Nomura, Yasuyuki. N1 - Funding Information: We thank Dr. Keiji Tanaka (Tokyo Metropolitan Institute of Medical Science), Dr. Hiroyuki Kawahara, and Prof. Hideyoshi Yokosawa (Hokkaido University) for the provision of plasmids and their helpful discussions. This work was supported by a Grant-in-Aid from the Ministry of Education, Science, and Sports of Japan.. PY - 2004/5/21. Y1 - 2004/5/21. N2 - Mammalian cells acquire tolerance against multiple stressors through the high-level expression of stress-responsible genes. We have previously demonstrated that protein-disulfide isomerase (PDI) together with ubiquilin are up-regulated in response to hypoxia/brain ischemia, and play critical roles in resistance to these damages. We show here that ubiquilin interacts preferentially with ...
The ubiquitin ligase (E3) Rsp5p is the only member of the Nedd (neural-precursor-cell-expressed, developmentally down-regulated) 4 family of E3s present in yeast. Rsp5p has several proteasome-independent functions in membrane protein trafficking, including a role in the ubiquitination of most plasma membrane proteins, leading to their endocytosis. Rsp5p is also required for the ubiquitination of endosomal proteins, leading to their sorting to the internal vesicles of MVBs (multivesicular bodies). Rsp5p catalyses the attachment of non-conventional ubiquitin chains, linked through ubiquitin Lys-63, to some endocytic and MVB cargoes. This modification appears to be required for efficient sorting, possibly because these chains have a greater affinity for the ubiquitin-binding domains present within endocytic or MVB sorting complexes. The mechanisms involved in the recognition of plasma membrane and MVB substrates by Rsp5p remain unclear. A subset of Rsp5/Nedd4 substrates have a PY motif and are ...
Protein ubiquitylation is a key process in the regulation of many cellular processes. The balance between the activity of ubiquitin ligases and that of proteases controls the level of ubiquitylation. In response to extracellular stimuli, stress-activated protein kinases (SAPK) modulate gene expression to maximize cell survival. In yeast, the Hog1 SAPK has a key role in reprogramming the gene expression pattern required for cell survival upon osmostress. Here, we show that the Ubp3 ubiquitin protease is a target for the Hog1 SAPK to modulate gene expression. ubp3 mutant cells are defective in expression of osmoresponsive genes. Hog1 interacts with and phosphorylates Ubp3 at serine 695, which is essential to determine the extent of transcriptional activation in response to osmostress. Furthermore, Ubp3 is recruited to osmoresponsive genes to modulate transcriptional initiation as well as elongation. Therefore, Ubp3 activity responds to external stimuli and is required for transcriptional ...
and mouse models of SMA. UBA1-associated disruption of β-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of β-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent β-catenin signaling, highlighting ubiquitin homeostasis and β-catenin as potential therapeutic targets for SMA. ...
TY - JOUR. T1 - The immunosuppressive activity and solution structures of ubiquitin fragments. AU - Jaremko, Lukasz. AU - Jaremko, Mariusz. AU - Pasikowski, Paweł. AU - Cebrat, Marek. AU - Stefanowicz, Piotr. AU - Lisowski, Marek. AU - Artyin, Jolanta. AU - Zimecki, Michał. AU - Zhukov, Igor. AU - Szewczuk, Zbigniew. PY - 2009/8/3. Y1 - 2009/8/3. N2 - Recently, ubiquitin was suggested as a promising antiinflammatory protein therapeutic. We found that a peptide fragment corresponding to the ubiquitin50-59 sequence (LEDGRTLSDY) possessed the immunosuppressive activity comparable with that of ubiquitin. CD and NMR spectroscopies were used to determine the conformational preferences of LEDGRTLSDY in solution. The peptide mixture, obtained by pepsin digestion of ubiquitin, was even more potent than the intact protein. Although the peptide exhibited a well-defined conformation in methanol, its structure was distinct from the corresponding 50-59 fragment in the native ubiquitin molecule.. AB - ...
DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional ...
During ubiquitination, Ub is initially activated by an ATP‐dependent E1 enzyme before it is passed to one of several distinct Ub‐conjugating enzymes (E2s). The E2 subsequently acts to either transfer Ub to a HECT (homologous to the E6AP carboxyl terminus)‐type Ub ligase (E3), or to catalyse substrate ubiquitination in conjunction with RING (really interesting new gene)‐type or U‐box E3 enzymes. An exception to this is the process of coupled monoubiquitination, through which E2 enzymes can catalyse the ubiquitination of Ub‐binding domain (UBD)‐containing proteins independently of E3 (Hoeller et al, 2006, 2007).. Ubiquitin ligases seem to be the crucial determinants of substrate selection and are also considered to be important components in controlling Ub‐chain formation on a substrate. For example, different HECT‐type E3s can specify both the linkage of a Ub chain and the process of its assembly. E6AP can form a Lys 48‐linked chain on its active cysteine residue (Scheffner & ...
We considered two possible explanations for the stu1-5 ubp3Δ synthetic lethality. First, we examined the possibility that Ubp3p plays a role in the cell-cycle regulation of Stu1p. Several mitotic proteins are subject to cell-cycle regulation involving ubiquitin-mediated protein degradation. However, the levels of Stu1p are relatively constant throughout the cell cycle, indicating that it is not a substrate for this specific ubiquitin-dependent pathway.. Next, we considered the possibility that mutant Stu1-5p is an unstable protein that is targeted for ubiquitin-mediated degradation. We showed that the levels of Stu1p in stu1-5 cells are several-fold lower than the levels in wild-type cells. In addition, the temperature sensitivity of stu1-5 can be suppressed by producing wild-type levels of the mutant protein. These results indicate that the temperature sensitivity is caused by reduced levels of Stu1p and not by reduced function. Interestingly, the critical threshold of Stu1-5p protein level ...
Project title: Regulation and control of linear ubiquitin chian synthesis: Structure, function and mechanism of linear ubiquitin chian assembly complex LUBAC. Summary: The linear ubiquitin chain assembly complex LUBAC is E3 ubiquitin ligase that plays pivotal roles in the innitiation of innate and adpative immune response, especially in the activation of nuclear factor-kappa B, which is a transcription factor that induces transcription of inflammatory genes. Abberrant LUBAC activity has been known as a contributor to diffuse large B-cell lymphoma (DLBL), which is a bone marrow malignancy. More importantly, individuals carrying congenital mutaions in LUBAC protein domains (i.e. HOIP, HOIL-1, SHARPIN) manifest devastating immunodeficiency and/or autoinflammatory symptoms. All those add up to the fact that LUBAC is really interesting and important. This project aims to unveal regulatory mechanisms for LUBAC activity with aid from biochemical and structural biology techiniques (i.e. in vitro protein ...
2879 The ubiquitin-proteasome pathway controls the turnover of many oncoproteins and tumor suppressors, thus playing a major role in cancer development. This pathway also regulates the stability of Smads. Recent studies have shown that R-Smads are post-translationally modified by ubiquitin and can be irreversibly removed from the cell by the proteasome-mediated degradation system. Ubiquitination, the covalent attachment of ubiquitin to proteins, predominantly serves to target proteins for their degradation by 26S proteasomes. Conjugation of ubiquitin is accomplished by an enzymatic cascade involving E1, E2 and E3 enzymes. Ubiquitin E3 ligases play the most significant role in substrate specificity. Smad4/DPC4 is a common signal transducer in TGF-β signaling. Contrary to R-Smads, our knowledge on the regulation of Smad4 by ubiquitin/proteasome pathway is rather limited. Although the ubiquitin-proteasome pathway has been established as one mechanism of regulating Smad4 stability, the specific ...
Protein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to proteins being degraded is performed by a reaction cascade consisting of three enzymes, named E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme), and E3 (ubiquitin ligase). Each E3 has specificity to its substrate, or proteins to be targeted by ubiquitination. Many E3s are discovered in eukaryotes and they are classified into four types: HECT type, U-box type, single RING-finger type, and multi-subunit RING-finger type. Multi-subunit RING-finger E3s are exemplified by cullin-Rbx E3s and APC/C. They consist of a RING-finger-containing subunit (RBX1 or RBX2) that functions to bind E2s, a scaffold-like cullin molecule, adaptor proteins, and a target recognizing subunit that binds substrates ...
Protein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to proteins being degraded is performed by a reaction cascade consisting of three enzymes, named E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme), and E3 (ubiquitin ligase). Each E3 has specificity to its substrate, or proteins to be targeted by ubiquitination. Many E3s are discovered in eukaryotes and they are classified into four types: HECT type, U-box type, single RING-finger type, and multi-subunit RING-finger type. Multi-subunit RING-finger E3s are exemplified by cullin-Rbx E3s and APC/C. They consist of a RING-finger-containing subunit (RBX1 or RBX2) that functions to bind E2s, a scaffold-like cullin molecule, adaptor proteins, and a target recognizing subunit that binds substrates ...
HPK1, a member of mammalian Ste20-like serine/threonine kinases, is lost in |95% pancreatic cancer through proteasome-mediated degradation. However, the mechanism of HPK1 loss has not been defined. The aims of this study are to identify the ubiquitin ligase and to examine the mechanisms that targets HPK1 degradation. We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome. The ubiquitination of HPK1 required its kinase activity and autophosphorylation. Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1 and Fbxw8-mediated ubiquitination of HPK1. In addition, we showed that Thr-355 of HPK1 is a key PP4 dephosphorylation site, through which CUL7/Fbxw8 ubiquitin ligase and PP4 regulates HPK1 stability. Knockdown of Fbxw8 restores endogenous HPK1 protein expression and inhibits cell proliferation of pancreatic cancer cells. Our study demonstrated that targeted degradation of HPK1 by
Antibodies for proteins involved in ubiquitin-dependent protein catabolic process pathways, according to their Panther/Gene Ontology Classification
Ubiquitin was detected within both the cytoplasm and nucleus of the cytotrophoblast layer only. Both monomeric and conjugated forms of ubiquitin were detected. The relative abundance of ubiquitin did not change through gestation or in the two disorders of pregnancy studied. This is the first report to demonstrate the cell-specific localisation of ubiquitin and ubiquitin-protein conjugates in the human cytotrophoblast and provides supportive evidence that ubiquitin may be important during placental development. PMID: 11742419 ...
Predicted to have ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Predicted to be involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; protein polyubiquitination; and ubiquitin-dependent protein catabolic process. Predicted to localize to mitochondrial membrane and ubiquitin ligase complex. Orthologous to human RNF144B (ring finger protein 144B ...
Irecently returned from the 2013 EMBO Conference on Ubiquitin and Ubiquitin‐like proteins: from structure to function, where I once again marveled at the rapid pace of discovery. From one year to the next, many people have completely new stories to tell and the spirit of the field is one of openness and collegiality. The late Cecile Pickart, a pioneer in ubiquitin research, once referred to ubiquitin as infinitively seductive. I have to agree, in more ways than one. Not only is ubiquitin involved in virtually all aspects of cell biology, but the community goes about its business in a very positive and welcoming manner; an approach not always seen in other areas of the biomedical sciences.. Given the rate at which new knowledge is acquired, and seeing the wealth of primary research published, we were inspired last year to put together a Review Series on Ubiquitylation: mechanism and functions. Some aspects of the latest research were not included-such as the role of ubiquitin in DNA repair, ...
Ubiquitin signaling pathways rely on E3 ligases for effecting the final transfer of ubiquitin from E2 ubiquitin conjugating enzymes to a protein target. Here we re-evaluate the hybrid RING/HECT mechanism used by the E3 family RING-between-RINGs (RBRs) to transfer ubiquitin to substrates. We place RBRs into the context of current knowledge of HECT and RING E3s. Although not as abundant as the other types of E3s (there are only slightly more than a dozen RBR E3s in the human genome), RBRs are conserved in all eukaryotes and play important roles in biology. Re-evaluation of RBR ligases as RING/HECT E3s provokes new questions and challenges the field.
The herpes simplex virus type 1 (HSV-1) encoded E3 ubiquitin ligase, infected cell protein 0 (ICP0), is required for efficient lytic viral replication and regulates the switch between the lytic and latent states of HSV-1. As an E3 ubiquitin ligase, ICP0 directs the proteasomal degradation of several cellular targets, allowing the virus to counteract different cellular intrinsic and innate immune responses. In this review, we will focus on how ICP0s E3 ubiquitin ligase activity inactivates the host intrinsic defenses, such as nuclear domain 10 (ND10), SUMO, and the DNA damage response to HSV-1 infection. In addition, we will examine ICP0s capacity to impair the activation of interferon (innate) regulatory mediators that include IFI16 (IFN γ-inducible protein 16), MyD88 (myeloid differentiation factor 88), and Mal (MyD88 adaptor-like protein). We will also consider how ICP0 allows HSV-1 to evade activation of the NF-κB (nuclear factor kappa B) inflammatory signaling pathway. Finally, ICP0s ...
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Ubiquitination was surprising because tBid-N has no lysine residues that conventionally act as ubiquitin acceptor sites (Fig. S1 B). Typically, ubiquitin can be linked either via a peptide bond to the ε amino group of a lysine residue or to the α amino group of an N-terminal residue (Ciechanover and Ben-Saadon, 2004). Because linkage to lysine was excluded, we investigated whether the N terminus of tBid-N acted as a ubiquitin acceptor site. To this end, tBid-N was fused C-terminally to a tandem affinity purification (TAP) tag, which contains a calmodulin-binding domain and protein A sequence separated by a tobacco etch virus (TEV) protease-sensitive site (ENLYFQG). This allows for two-step purification; first on IgG beads and then after cleavage by TEV on calmodulin beads (Rigaut et al., 1999). In one tBid-N TAP construct (TEV tBid-N TAP 7), sequences encoding the first seven amino acids of tBid-N and a TEV protease site were cloned upstream of the tBid-N coding region (Fig. 3 C). If tBid-N ...
Following a map-based approach, we cloned HVE and found it to encode the Arabidopsis ortholog of mammalian CAND1. The important role of the HVE/CAND1 gene in vascular development has remained unnoticed so far, even though its cloning and the characterization of several mutant alleles have been reported by three research groups (Cheng et al., 2004; Chuang et al., 2004; Feng et al., 2004). Human CAND1 regulates the ubiquitination of target proteins by binding to unneddylated CULLIN1 (CUL1). CUL1, SKP1 and F-box proteins form SCF complexes that ligate ubiquitin moieties to proteins that will be degraded by the 26S proteasome. It has been proposed that the binding of CAND1 to unneddylated CUL1 hinders the interaction of SKP1 with CUL1 preventing the assembly of the SCF complex. After neddylation of CUL1, CAND1 is released and the SFC complex is assembled (Liu et al., 2002; Zheng et al., 2002; Hwang et al., 2003; Oshikawa et al., 2003).. Ubiquitin-mediated protein degradation is essential for auxin ...
Ubiquitin regulation appears to have an important but not well-understood role in C. elegans embryonic polarization. One of the earliest discoveries was that PAR-2 has homology to RING domain E3 ubiquitin ligases, suggesting that ubiquitin ligase activity may be important for excluding anterior PARs from the posterior [5], [37]. Hao and colleagues showed that the PAR-2 RING domain is required for robust transgene rescue of embryos lacking endogenous PAR-2, indicating that it is likely to be an active ubiquitin ligase in vivo, although this activity is not absolutely essential for function [25]. Biochemical targets of PAR-2, however, are unknown. Other results that relate ubiquitin-based regulation to polarization include the finding that PAR-6 levels are affected by activity of the ubiquitin ligase CUL-2 and its adapter protein FEM-3 [44], and that mutations of C. elegans homologs of the BRAT family of ubiquitin ligases have been shown to be able to suppress weak par-2 phenotypes [45]. Weak ...
TY - JOUR. T1 - Ubiquitin ligases. T2 - Cell-cycle control and cancer. AU - Nakayama, Keiichi I.. AU - Nakayama, Keiko. PY - 2006/5/1. Y1 - 2006/5/1. N2 - A driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs), the activities of which are controlled by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors. Two ubiquitin ligases, the SKP1-CUL1-F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), are responsible for the specific ubiquitylation of many of these regulators. Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.. AB - A ...
Ubiquitin-dependent regulation of endocytosis plays an important part in the control of signal transduction, and a critical issue in the understanding of signal transduction therefore relates to regulation of ubiquitination in the endocytic pathway. We discuss here what is known of the mechanisms by which signaling controls the activity of the ubiquitin ligases that specifically recognize the targets of ubiquitination on the endocytic pathway, and suggest alternative mechanisms that deserve experimental investigation.
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm.[1] The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that carry out such reactions are called proteases. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into amino acids and used in synthesizing new proteins.[2] Proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. Once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin molecules. The result is a polyubiquitin chain that ...
MalaCards based summary : Itch E3 Ubiquitin Ligase Deficiency, also known as autoimmune disease, syndromic multisystem, is related to autoimmune disease, multisystem, with facial dysmorphism and autoimmune disease. An important gene associated with Itch E3 Ubiquitin Ligase Deficiency is ITCH (Itchy E3 Ubiquitin Protein Ligase). Affiliated tissues include liver and thyroid ...
Ubiquitin-binding protein that interacts with the BRCA1-BARD1 heterodimer, and regulates its activity. Specifically binds Lys-6-linked polyubiquitin chains. Interaction with autoubiquitinated BRCA1, leads to inhibit the E3 ubiquitin-protein ligase activity of the BRCA1-BARD1 heterodimer. Component of a complex required to couple deglycosylation and proteasome-mediated degradation of misfolded proteins in the endoplasmic reticulum that are retrotranslocated in the cytosol ...
ubiquitin protein ligase activity, proteasome-mediated ubiquitin-dependent protein catabolic process, protein polyubiquitination, protein ubiquitination involved in ubiquitin-dependent protein catabolic process
Ubiquitin과 Protein의 접합은 Stability와 Activity, Localization 등의 환경에 의해 변화할 수 있습니다.. 거의 모든 Protein은 Life cycle의 어느 시점에 Ubiquitylated 되지만, 3 종류의 Enzyme이 관여하게 됩니다.. E1 Activating enzyme은 Ubiquitin을 E2 Conjugation enzyme에 전달하거나 활성화시킵니다.. 이후 E2 Enzyme은 E3 Ligase 도움하에 직, 간접적으로 Ubiquitin을 기질로 보내며 E3는 기질 단백질에 결합하여 강한 선택성을 가지고 Ubiquitination으로 표지할 기질단백질을 인지합니다.. Deregulated E3 ligase는 암, 바이러스 감염, 관절염 등 다양한 부분에 심각한 질병을 일으킵니다.. 따라서 이러한 연구는 혁신적인 치료제 개발에 많은 도움을 줄 것입니다. ...
Ubiquitination is a post-translational modification in which one or more 76 amino acid polypeptide ubiquitin molecules are covalently linked to the lysine residues of target proteins. Ubiquitination is the main pathway for protein degradation that governs a variety of eukaryotic cellular processes, including the cell cycle, vesicle trafficking, antigen presentation and signal transduction. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of many diseases including inflammatory and neurodegenerative disorders. Recent studies have revealed that viruses and bacterial pathogens exploit the host ubiquitination pathways to gain entry and to aid their survival/replication inside host cells. This review will summarize recent developments in understanding the biochemical and structural mechanisms utilized by bacterial pathogens to interact with the host ubiquitination pathways.
Ubiquitin binding of OspG is required for inhibiting host NF-κB signaling during Shigella infection.(A) The role of OspG in recruitment of ubiquitin to intrace
Endosomal protein that forms a complex with Hse1p; required for recycling Golgi proteins, forming lumenal membranes and sorting ubiquitinated proteins destined for degradation; has Ubiquitin Interaction Motifs which bind ubiquitin (Ubi4p ...
Antibodies for proteins involved in free ubiquitin chain depolymerization pathways, according to their Panther/Gene Ontology Classification
Chemical Synthesis of Ubiquitinated Peptides with Varying Lengths and Types of Ubiquitin Chains to Explore the Activity of Deubiquitinases | Dr. Sudhir N. Bavikar; Liat Spasser; Mahmood Haj-Yahya; Dr. Subramanian Vedhanarayanan Karthikeyan; Tal Moyal; Dr. K. S. Ajish Kumar; Prof. Ashraf Brik | download | BookSC. Download books for free. Find books
TY - JOUR. T1 - Modulating cellular balance of Rps3 mono-ubiquitination by both Hel2 E3 ligase and Ubp3 deubiquitinase regulates protein quality control. AU - Jung, Youjin. AU - Kim, Hag Dong. AU - Yang, Hee Woong. AU - Kim, Hye Jin. AU - Jang, Chang Young. AU - Kim, Joon. PY - 2017/11/3. Y1 - 2017/11/3. N2 - When a ribosome complex is stalled during the translation elongation process in eukaryotes, the mono-ubiquitination of Rps3 has recently been shown to be critical to ribosome quality control. We have discovered that the regulatory role of Rps3 mono-ubiquitination is controlled by a deubiquitinase. We also showed that an autophagic signal appears to be coupled to the mono-ubiquitination of Rps3p through the entrance of Ubp3p into the autophagosome in yeasts. The mono-ubiquitination of the Rps3 protein is tightly modulated by reciprocal action between the Hel2p E3 ligase and the Ubp3p deubiquitinase in yeasts and the reciprocal action between the RNF123 E3 ligase and the USP10 deubiquitinase ...
May be involved in nucleotide excision repair (By similarity). Binds and presumably selects ubiquitin-conjugates for destruction. Prefers multiubiquitin chains rather than single ubiquitins, with a binding affinity for Lys-48-linked ubiquitin chains. Acts as a ubiquitin receptor that associates with the 26S proteasomal docking subunit RPN10 for the indirect recognition of ubiquitinated substrates of ubiquitin/26S proteasome-mediated proteolysis (UPP).
PDCD5 mediates ubiquitin-dependent proteasomal degradation of HDAC3 via C-terminal cleavage of HDAC3.(a) MG132 treatment induces accumulation of cleaved HDAC3.
Protein turnover is crucial in maintaining cellular homeostasis and this process is largely controlled by the Ubiquitin Proteasome Pathway (UPP). The pathway consists of an enzymatic cascade that links the polypeptide cofactor Ubiquitin to specific protein targets, which mark them for degradation by the proteasome. This cascade is highly regulated and impacts virtually all cellular processes including cell cycle progression, cell proliferation, cell differentiation and apoptosis. Malfunction of the UPP has been implicated in the development of diseases such as cancer, immune disorders and neurodegeneration. ...
Research in the field of ubiquitin proteasome is expanding exponentially. For instance, intensive research is going on in the field of applications of ubiquitin proteasome system in the treatment of cancer, as the pharmacological inhibition properties of proteasomes can be effective in cancer treatment. Potential sites of therapeutic interventions are also under research and the selective inhibition of disease specific components is also being studied for the purpose of developing treatments for diseases such as neurodegenerative disorders. This indicates a bright future market potential depending upon the time required for commercialization. Currently, there is only one approved ubiquitin proteasome system product available in the market named Velcade. In 2009, total sales of Velcade were estimated to be 1.4 billion and being the only approved drug, its sales are expected to achieve growth at a high compounded annual growth rate ...
TY - JOUR. T1 - Stable ester conjugate between the Saccharomyces cerevisiae RAD6 protein and ubiquitin has no biological activity. AU - Sung, Patrick. AU - Prakash, Satya. AU - Prakash, Louise. PY - 1991/10/5. Y1 - 1991/10/5. N2 - The RAD6 gene of Saccharomyces cerevisae, which encodes a ubiquitin-conjugating enzyme, is required for DNA repair, DNA damage-induced mutagenesis and sporulation. To evaluate the biological relevance of the thioester adduct between RAD6 protein and ubiquitin, formed as an obligatory, transient intermediate during ubiquitin conjugation to substrates, we 3ltered cysteine 88 in RAD6 to serine. Esterification with ubiquitin occurs at serine 88 in the mutant protein, but conjugation of ubiquitin to the test substrate histone H2A is inactivated. Phenotypically, strains harboring the rad6 Ser88 allele are indistinguishable from rad6 deletion (rad6Δ) mutant cells. These findings argue against ligation of ubiquitin at cysteine 88 acting as a functional switch of a cryptic ...
CIECHANOVER, Aaron. Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Medicina (B. Aires) [online]. 2010, vol.70, n.2, pp. 105-119. ISSN 0025-7680.. Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely non-lysosomal, but the mechanisms involved remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of ...
F-box proteins serve as mediators in targeting bound target proteins for ubiquitination and destruction. The ubiquitin-dependent proteolytic pathway plays a key role in the regulation of various short-lived proteins involved in diverse cellular processes in eukaryotes including cell cycle progression, morphogenesis, signal transduction and transcription regulation[11, 12]. The primary function of the ubiquitin-dependent proteolytic system is the tagging of substrate proteins with ubiquitin, i.e. covalent attachment of multiple ubiquitin molecules, which allows the proteasome, a 26S protease complex, to recognize and degrade target proteins. This process involves several main steps: (1) activation of ubiquitin in a thioester linkage with ubiquiin-activating enzyme (E1); (2) ransfer of activated ubiquitin from E1 to active site cysteine of one of many ubiquitin-conjugated enzymes (E2s); and finally, (3) conjugation of ubiquitin mainly to acceptor lysine residue of the target protein forming the ...
The attachment of one or more ubiquitin moieties to proteins plays a central regulatory mechanism in eukaryotic cells. Protein ubiquitylation regulates numerous cellular processes, including protein degradation, signal transduction, DNA repair and cell division. The characterization of ubiquitylation is a two-fold challenge that involves the mapping of ubiquitylation sites and the determination of ubiquitin chain topology. This review focuses on the technical advances in the mass spectrometry-based characterization of ubiquitylation sites, which have recently involved the large-scale identification of ubiquitylation sites by peptide-level enrichment strategies. The discovery that ubiquitylation is a widespread modification similar to phosphorylation and acetylation suggests cross-talk may also occur at the post translational modification level ...
Alexander Varshavsky, Caltechs Thomas Hunt Morgan Professor of Biology, has received the 2017 Heinrich Wieland Prize from the Boehringer Ingelheim Foundation. The prize, named after the late Nobel Laureate Heinrich Wieland, honors outstanding research on biologically active molecules and systems in the fields of chemistry, biochemistry, and physiology as well as their clinical importance.. Varshavsky was recognized for his work on the biology of the ubiquitin system, a large set of molecular pathways that have in common a small protein called ubiquitin. A major function of the ubiquitin system is the regulated degradation of cellular proteins. The ubiquitin system targets for selective destruction not only misfolded or otherwise abnormal proteins, but also normal proteins that have evolved to be short-lived, depending on specific physiological conditions. The destruction of such proteins underlies a multitude of biological processes, including cell growth and division, cell differentiation, ...
Ubiquitin received its name because of its ubiquitous expression in eukaryotic cells. Since its discovery more than 40 years ago, the covalent attachment of ubiquitin to proteins has become well established as a degradative signal. However, more recently it has become clear that protein degradation is only one of many processes regulated by ubiquitylation and it has emerged that this 76 amino acid protein is also crucial for the regulation of numerous cellular processes. For example, ubiquitin is also involved in endocytosis, membrane trafficking, DNA repair, and the regulation of signalling pathways and the cell cycle. In this issue, we conclude our Ubiquitin Minifocus with three articles that provide further insight into the diverse roles of ubiquitylation. E3 ubiquitin ligases are central to the post-translational modification of proteins with ubiquitin and - in a Cell Science at a Glance article (p. 531) - Meredith Metzger, Ventzislava Hristova and Allan Weissman provide an overview of the ...
E3 ubiquitin ligases have a significant role in carcinogenesis and include a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome. ubiquitin ligases for GC are discussed IPI-493 in the review. (a very interesting new gene) fingers IPI-493 and U-box domains[21]. There are about 30 proteins containing the HECT domain. The fingers and U-box quitin ligases contain the new gene (finger domain but only a small part functions as an E3 ubiquitin ligase. Unlike RING proteins most HECT proteins if not all are believed to function as E3 ubiquitin ligases. RING and HECT E3 ubiquitin ligases use different catalytic mechanisms to promote the transfer of ubiquitin to targeted substrates. RING E3 ubiquitin ligases can promote the direct transfer of ubiquitin from E2 to the targeted substrate whereas HECT E3 ubiquitin ligases interact with the cognate E2 followed by the formation of a thiolester linkage with ubiquitin and subsequent ...
FUNCTION: This gene encodes a protein that is a member of the ubiquitin C-terminal hydrolase subfamily of the deubiquitinating enzyme family. Members of this family catalyze the removal of ubiquitin from a substrate or another ubiquitin molecule and thereby play important roles in regulating signaling pathways, recycling ubiquitin and regulating protein stability. This protein removes ubiquitin from K-63-linked ubiquitin chains from proteins involved in NF-kappaB signaling and thus acts as a negative regulator of this pathway. In humans mutations in this gene have been associated with cylindromatosis, an autosomal dominant predisposition to tumors of skin appendages. In mouse deficiency of this gene impairs thymocyte development and increases susceptibility to skin and colon tumors. A pseudogene of this gene has been identified on chromosome 1. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jan 2013 ...
Polyubiquitin chains are composed of ubiquitin monomers that are covalently linked through isopeptide bonds (other than linear, or Met1-linked polyubiquitin). Isopeptides are formed between a lysine residue of one Ubiquitin molecule and the C--terminal glycine residue of another Ubiquitin molecule. Seven of the seventy-six amino acids in ubiquitin are lysine residues that can participate in polyubiquitin chain formation. Linkage through specific lysine residues is thought to serve as a signal that affects protein degradation, signaling, trafficking, and other cellular processes. K48-linked polyubiquitin chains attached to substrate proteins often serve as a recognition sequence for targeting and destruction of the substrate by the 26S Proteasome. This antibody detects the K48 linkage. It does not detect monoubiquitin or ubiquitin liked via any other lysine residue. Reactivity across all species is anticipated. ...
Anti-Mono and Polyubiquitylated Conjugates mAb (FK2) HRP-linked Antibody Activity Assay: The activity of the anti-mono and polyubiquitylated conjugates mAb (FK2) HRP-linked antibody was tested for its ability to recognise mono and polyubiquitin conjugates (Lanes 2 and 3) but not free ubiquitin (Lane1). By Western blotting the specific recognition of mono and polyubiquitin conjugates by the antibody over free ubiquitin was demonstrated (Figure 1). In a priming and extension assay containing, UBE1 [6His-tagged] (Cat# 61-0001), UBE2W [6His-tagged] (Cat# 62-0085), UBE2N [untagged] (Cat# 62-0047), UBE2V1 [untagged] (Cat# 62-0059), Ubiquitin (Cat# 60-0001), CHIP [untagged] (Cat# 63-0003) and ATP. Using the anti mono and polyubiquitylated conjugates mAb (FK2) HRP-linked antibody, detection of polyubiquitin chains extending from mono-ubiquitylated CHIP (Lane 1) and free chains generated by UBE2N/UBE2V1 in the presence of CHIP (Lane 3) were observed. In the absence of CHIP, only the background detection ...
In recent years a superfamily of ubiquitin-like domains has been identified [30]. This superfamily can be divided into the ubiquitin-like proteins (UBLs), which consist solely of the ubiquitin-like domain, and ubiquitin domain proteins (UDPs), which are larger proteins containing one or more ubiquitin-like domains. To our knowledge DWNN is the first example of a ubiquitin-like domain that is alternatively expressed both as a UBL and as a UDP.. Ubiquitin-like proteins typically share the C-terminal GG motif, which acts as a recognition motif for a protease that cleaves between the two glycines, initiating the process of conjugation. The occurrence of the GG motif in the structurally identical position in human and mouse DWNN domains (highlighted in pink in Figure 4D) suggests that the domain may be involved in a similar process of conjugation, which we may call DWNNylation. As in the case of ubiquitin, the GG lies outside of the structured region, as can be clearly seen in Figure 5B. The ...
Doss-Pepe, E.W., et al. (2003). Ataxin-3 interactions with Rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis. Mol. Cell. Biol 23(18): 6469-6483. ...
Phytohormone abscisic acid (ABA) regulates key processes in plants relative to seed germination, plant development and responses to important environmental stresses, such as drought, salinity and extreme temperatures. ABA perception is tightly controlled by the ubiquitin proteasome system. CRL4-CDDD E3 ubiquitin ligases target ABA receptors of the PYR/PYL/RCAR (pyrabactin resistance/pyrabactin resistance-like/regulatory components of ABA) family, triggering their ubiquitination and proteasomal degradation. Therefore, CRL4-CDDD complexes function as repressors of ABA-mediated stress responses. On the contrary, ABA treatment attenuates receptor degradation although the precise molecular details of this mechanism have remained unknown. In this seminar, our most recent data on the regulatory process underlying ABA-mediated protection of PYR/PYL/RCAR receptors, by CRL4-CDDD E3 ubiquitin ligases inactivation, will be shown.. ...
In the ubiquitin-mediated pathway for the degradation of intracellular proteins, several molecules of ubiquitin are linked to the protein substrate by amide linkages. It was noted that the number of ubiquitin-protein conjugates and their apparent molecular size are higher than expected from the number of amino groups in the protein. When the amino groups of ubiquitin were blocked by reductive methylation, it was efficiently conjugated to lysozyme, but the higher-molecular-weight conjugates were not formed. This suggests that the higher-molecular-weight conjugates with native ubiquitin contain structures in which one molecule of ubiquitin is linked to an amino group of another molecule of ubiquitin. Methylated ubiquitin stimulated protein breakdown at about one half the rate obtained with native ubiquitin, and isolated conjugates of 125I-lysozyme with methylated ubiquitin were broken down by reticulocyte extracts. These findings indicate that the formation of polyubiquitin chains is not ...
Exit from mitosis requires the degradation of regulatory proteins including the mitotic cyclins and securin through ubiquitination by the anaphase promoting complex bound to Cdc20 or Cdh1. Cdc20-APC is regulated through inhibition by the spindle assembly checkpoint protein MAD2. Knowledge of Cdh1-APC regulation is limited to the phosphorylation-dependent dissociation of Cdh1 from APC. A novel means of regulating Cdh1 by the MAD2-related gene, MAD2L2, is reported. MAD2L2 specifically binds and inhibits Cdh1-APC, paralleling the effect of MAD2 on Cdc20. It is suggested that MAD2L2 and MAD2 inhibit the release of substrates from APC and a mechanism of inhibition is proposed (Pfleger, 2001a). The specificity of ubiquitin-mediated protein degradation with regard to the selection of substrates to be polyubiquitinated has only been determined rather recently. Substrate targeting by the N-end rule and HECT (homology to E6AP carboxyl terminus) domain ubiquitin ligases occurs through substrate-specific ...
The selective degradation of many proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved protein [1]. Ubiquitylated proteins were degraded by the 26S protea-some in an ATP-depended manner. The degradation of ubiquitylated proteins were controlled by isopeptidase cleavage. A well characterised system of ubiquitylation and deubiquitylation is the calmodulin system in vitro [2]. Detection of ubiquityl-calmodulin conjugtates in vivo have not been shown so far. In this article we discuss the detection of ubiquitin calmodulin conjugates in vivo by incubation with a novel high-molecular weight ubiquitylprotein-isopeptidase in rabbit tissues. Proteins with a molecular weight of ubiquityl-calmodulin conjugates could be detected in all organs tested. Incubation with ubiquitylprotein-isopeptidase showed clearly a decrease of ubiquitin calmodulin conjugates in vivo with an origination of
The majority of eukaryotic proteins are degraded by the ubiquitin-proteasome system. In this pathway, cytosolic substrates are first earmarked for degradation by modification with ubiquitin (ubiquitylation) and subsequently degraded by the 26S pro-teasome, a large protease residing in both the cytosol and the nucleus. ER-resident proteins are similarly degraded but take the route of a specialized pathway coined ER-associated degradation (ERAD). In order to reach the cytosolic ubiquitin/proteasome system, these substrates must first relocate from the ER to the cytosol, possibly with the help of protein conducting membrane channels. Previous work has shown that specific ubiquitin-conjugating enzymes (e.g. Ubc6, Ubc7) and ubiquitin ligases (e.g. Hrd1) con-tribute to ERAD, but how the substrates reach the proteasome remained to be clarified. Besides its function as a quality control system in recognizing and eliminating aberrant proteins, ERAD appears also to play a part in regulatory pathways. ...
Covalent attachment of ubiquitin (Ub) or SUMO to DNA repair proteins plays critical roles in maintaining genome stability. These structurally related polypeptides can be viewed as distinct road signs, with each being read by specific protein interaction motifs. Therefore, via their interactions with selective readers in the proteome, ubiquitin and SUMO can elicit distinct cellular responses, such as directing DNA lesions into different repair pathways. On the other hand, through the action of the SUMO-targeted ubiquitin ligase (STUbL) family proteins, ubiquitin and SUMO can cooperate in the form of a hybrid signal. These mixed SUMO-ubiquitin chains recruit
The SIAH1 gene encodes a RING-type E3 ubiquitin ligase belonging to the Seven in Absentia Homolog (SIAH) family. The enzyme carries out the ubiquitination of a wide variety of targets, either by direct binding or by acting as the essential RING domain subunit for larger E3 ubiquitin ligase complexes. By carrying out its function, the protein marks its targets for proteasomal degradation. Target substrates of SIAH1 include transcription regulators such as ELL2, MYB, POU2AF1, PML and RBBP8, the signal transduction molecules TIEG1 and NUMB, the cell surface receptor DCC and the anti-aopoptotic protein BAG1. It also ubiquitinates SYP, a protein involved in synaptic vesicle function in neurons. The protein is thus involved in the regulation of several key biological processes such as apoptosis, axon guidance, cell cycle, spermatogenesis and nervous system development. ...
Because NF-κB pathways make key contributions to host defense mechanisms, the activation of NF-κB is tightly controlled by endogenous regulators acting at several sites. Ubiquitination regulates at least four steps in NF-κB pathways, including targeting IκBα for degradation, processing of NF-κB precursors to produce p50/p52 subunits of NF-κB, and activation of kinases such as receptor-interacting protein or the regulatory subunit of the IKK complex IKKγ (NEMO) and activation of TRAF-family adapter proteins (TRAF2, TRAF6) (9, 35, 36). Ubiquitin is a 76-aa protein that is covalently attached to target proteins through an isopeptide bond, between the C terminus of ubiquitin and the ε-amino group of a lysine residue in the target proteins (9, 37). Ubiquitin contains seven lysine residues, but ubiquitin chains linked on Lys48 and Lys63 are the best characterized, to date. Whereas Lys48-linked polyubiquitin chains represent a signal for proteosomal degradation of modified substrates such as ...
Ubiquitin is an 8.5 kDa post-translational modifier involved in essentially all eukaryotic cellular processes. Through a process called ubiquitination, ubiquitinating enzymes chemically attach ubiquitin to substrate proteins to control their fates, resulting in anything from their recruitment into signaling pathways to their proteasomal degradation, with a plethora of possibilities in between. Ubiquitin molecules can also be attached to one another, resulting in poly-ubiquitin chains with various effects depending on the number of ubiquitin molecules and the specific amino acid residues used to link them together. While most poly-ubiquitin in the cell exists as conjugated species, there are also untethered poly-ubiquitin species that are not attached to substrates. These unanchored ubiquitin chains have been previously classified as toxic byproducts that interfere with proteasomal function in vitro and in yeast, and are thus believed to be disassembled rapidly to avoid toxicity. Conversely, several
A protein degradation pathway is found at the inner nuclear membrane that is distinct from, but complementary to, endoplasmic-reticulum-associated protein degradation, and which is mediated by the Asi protein complex; a genome-wide library screening of yeast identifies more than 20 substrates of this pathway, which is shown to target mislocalized integral membrane proteins for degradation. The endoplasmic-reticulum-associated protein degradation (ERAD) pathway mediates protein homeostasis in cells by tagging misfolded proteins of the ER with the protein ubiquitin. Ubiquitylated proteins are subsequently degraded within the cytoplasm. The nuclear membrane is continuous with the ER membrane, prompting Michael Knop and colleagues to ask whether protein quality control also operates in the inner nuclear membrane (INM). The authors find that there is a protein degradation pathway at the INM (mediated by the Asi protein complex) that is distinct from, but complementary to, the ERAD. An unbiased screening of a
Chain‐selective binding of the TAB2‐ and TAB3‐NZFs seems to be related to the hydrophilic Gln that is located in the position of Φ in the TF/Φ motif for ubiquitin binding. The Npl4‐ and Vps36‐NZF domains contain the complete TF/Φ motif (Φ is Met 570 in the Npl4‐NZF or Ile 199 in the Vps36‐NZF) where Phe and Φ form a hydrophobic surface to interact with the Ile 44‐centred hydrophobic patch of ubiquitin. In contrast, Φ is replaced by the hydrophilic Gln 686/709 in TAB2/TAB3 (Supplementary Figure S5A), which contributes little to the distal ubiquitin binding, as mentioned above (Figure 3).. To clarify the relationship between the monoubiquitin binding and Φ in the TF/Φ motif, we mutated Met 570 of the Npl4‐NZF and Ile 199 of the Vps36‐NZF to Gln, and also mutated Gln 686 of the TAB2‐NZF to Ile or Met for GST pull‐down analyses. Strikingly, the Q686M and Q686I mutations enabled the TAB2‐NZF to bind to monoubiquitin and resulted in linkage‐independent binding to ...
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code was transcribed to RNA and translated to proteins, but how proteins were degraded had remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis was largely non-lysosomal, but the mechanisms involved have remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led ...
Selective degradation of proteins in the cell occurs through ubiquitination, which consists of post-translational deposition of ubiquitin on proteins to target them for degradation by proteases. However, ubiquitination does not only impact on protein stability, but promotes changes in their functions. Whereas the deposition of ubiquitin has been amply studied and discussed, the antagonistic activity, deubiquitination, is just emerging and the full model and players involved in this mechanism are far from being completely understood. Nevertheless, it is the dynamic balance between ubiquitination and deubiquitination that is essential for the development and homeostasis of organisms. In this review, we present a detailed analysis of the members of the deubiquitinase (DUB) superfamily in plants and its division in different clades. We describe current knowledge in the molecular and functional characterisation of DUB proteins, focusing primarily on Arabidopsis thaliana. In addition, the striking function of
Intracellular protein degradation is mediated either by lysosomal proteolysis or by a ubiquitin-dependent process that targets unwanted proteins to proteasome. The ubiquitin/proteasome pathway in which many proteins result, is of vital importance for cellular homeostasis and hence for the organism itself. This post-translational modification requires the participation of three types of enzymes, E1 ubiquitin-activating enzyme, E2 conjugating enzyme and E3 ubiquitin ligase. The prominent role of E3 ligases is distinguished by the fact that it bridges the distance between the target protein and ubiquitin and thus mediating in covalent bonding; on the other hand, they are discerned for their high degree of specificity and selectivity concerning their substrates (E2 enzyme, target protein). Arkadia 2C/RNF165 protein belongs to the class of E3 ligases with a distinct zinc ion motif located at the C-terminal region. The RING finger domain is consisted of 41 amino acids and binds two Zn2+ in a unique ...
Ubiquitin-binding protein that specifically recognizes and binds Lys-63-linked ubiquitin. Does not bind Lys-48-linked ubiquitin. Positively regulates the internalization of ligand-activated EGFR by binding to the Ub moiety of ubiquitinated EGFR at the cell membrane ...
Background Ubiquitin is a Nobel Prize winning posttranslational protein modifier. The postranslational modification of proteins with the small protein called ubiquitin is a crucial step in a diverse subset of different cellular regulatory mechanisms. The best described function of ubiquitination is the subsequent degradation of modified proteins by either the 26S proteasome or the vacuole/lysosome. Abberations in these important mechanisms lead to severe diseases ranging from cancer to neurodegeneration. The attachment of ubiquitin to target proteins is therefore a highly regulated process. It is regulated by an enzymatic reaction cascade: First, ubiquitin gets activated and attached to a internal cysteine residue within the ubiquitin acivating enzyme (E1); second the activated ubiquitin is transferred to a internal cysteine of a ubiquitin conjugating enzyme (E2) and finally ubiquitin ligases (E3) allow either the direct transfer of ubiquitin to a lysine residue of a substrate protein (A) or are ...
Many cyanogen bromide cleavage protocols fail to cleave ubiquitin because of its stability in acid. The following protocol has proved effective for cleaving the ubiquitin mutant I36W P37M F45W. ...
A 58-residue-long, PEST-like sequence within the yeast a-factor receptor (Ste3p) specifies the ubiquitination, endocytosis, and consequent vacuolar degradation of the receptor protein (Roth, A. F., Sullivan, D. M., and Davis, N. G. (1998) J. Cell Biol. 142, 949-961). The present work investigates three lysyl residues that map within this sequence as the potential ubiquitin acceptor sites. Lys --> Arg substitution mutants were tested for effects on both ubiquitination and endocytosis. Results indicate that the three lysines function redundantly; a severe blockade to both ubiquitination and endocytosis is seen only for receptors having all three lysines replaced. Of the three, Lys(432) plays the predominant role; ubiquitination and turnover are significantly impaired for receptors having just the K432R mutation. CNBr fragmentation of the receptor protein, used for the physical mapping of the ubiquitin attachment sites, showed PEST-like sequence lysines to be modified both with single ubiquitin ...
Ubiquitination-the covalent conjugation of ubiquitin (Ub) to other cellular proteins-regulates a wide range of cellular processes. Often, multiple Ub molecules are added to the substrate to form a Ub chain. Distinct outcomes have been observed for substrates modified with multi-Ub chains linked through particular lysine residues. However, recent studies suggest that Ub chain linkages may not be the key determinant for substrate fate. Here, we review evidence suggesting that Ub-binding proteins play a pivotal role in determining the outcome of substrate ubiquitination. In fulfilling their functions in proteasome-mediated proteolysis or signaling, Ub receptors link ubiquitinated proteins to downstream molecules through protein-protein interactions. Studies of Ub-binding factors may therefore hold the key to understanding the diverse functions of the Ub molecule.. ...
This gene encodes an ubiquitin-like protein (ubiquilin) that shares a high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases, and thus are thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This ubiquilin has also been shown to modulate accumulation of presenilin proteins, and it is found in lesions associated with Alzheimers and Parkinsons disease. Two transcript variants encoding different isoforms have been found for this gene ...
Gene Information This gene encodes an ubiquitin-like protein (ubiquilin) that shares a high degree of similarity with related products in yeast rat and frog. Ubiquilins contain an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases and thus are thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This ubiquilin has also been shown to modulate accumulation of presenilin proteins and it is found in lesions associated with Alzheimer's and Parkinson's disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq Jul 2008]. ...
The ser-thr Akt plays a crucial role in the regulation of cell success cell growth and proliferation aswell as energy metabolism and it is dysregulated in lots of cancers. of IKKα in managing Akt activity and whether this might involve mTORC2. The tests display that IKKα affiliates with mTORC2 in a number of cancers cells in a way reliant on PI3K/Akt activity which IKKα favorably promotes Akt phosphorylation R935788 at Ser473 with Thr308. Furthermore IKKα enhances mTORC2 kinase activity aimed to Akt on Ser473 and Akt-mediated phosphorylation of FOXO3a and GSK3β however not additional Akt-associated targets such as for example TSC2 and PRAS40 indicating the lifestyle of multiple AFX1 systems of Akt activation in cells. In addition loss of IKKα suppresses growth factor-induced Akt activation associated with mTORC1 inhibition. These results indicate that IKKα serves as a feedforward R935788 regulator of mTORC2 and that IKKα could serve as a key therapeutic target to block mTORC2 and Akt ...
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Abstract: Cellular cross-talk between ubiquitination and other posttranslational modifications contributes to the regulation of numerous processes. One example is ADP-ribosylation of the carboxyl terminus of ubiquitin by the E3 DTX3L/ADP-ribosyltransferase PARP9 heterodimer, but the mechanism remains elusive. Here, we show that independently of PARP9, the conserved carboxyl-terminal RING and DTC (Deltex carboxyl-terminal) domains of DTX3L and other human Deltex proteins (DTX1 to DTX4) catalyze ADP-ribosylation of ubiquitins Gly76. Structural studies reveal a hitherto unknown function of the DTC domain in binding NAD+. Deltex RING domain recruits E2 thioesterified with ubiquitin and juxtaposes it with NAD+ bound to the DTC domain to facilitate ADP-ribosylation of ubiquitin. This ubiquitin modification prevents its activation but is reversed by the linkage nonspecific deubiquitinases. Our study provides mechanistic insights into ADP-ribosylation of ubiquitin by Deltex E3s and will enable future ...
We have shown that in human cells, an antiserum generated against a recombinant UBPY fragment recognizes a protein doublet of Mr 130 000, in good agreement with the predicted UBPY mol. wt of 127 500 Da. The UBPY bands were enhanced upon transfection of a sense UBPY cDNA and, most importantly, were lowered in abundance upon transfection of an antisense cDNA construct. UBPY was able to remove ubiquitin from ubiquitin adducts. Its expression was undetectable upon serum starvation of normal human fibroblasts, and the protein reappeared upon re‐stimulation, in mid G1 coincident with the accumulation of cyclin D1. UBPY levels were reduced in non‐immortalized cells as they reached confluence and arrested in G0, while they remained high and even increased in transformed cells.. To date, no other studies have demonstrated the effects of down‐regulating a UBP in mammalian cells. We have been able to inhibit UBPY accumulation using an antisense cDNA vector and could demonstrate that G0‐arrested ...
The HaloTag® fusion vectors are designed to be used as the fluorescent acceptor in NanoBRET™ assays that monitor interactions of a specific target protein along the UPS pathway.
634 The ubiquitin-proteasome pathway plays a major role in cancer development and is a bona fide target for cancer therapy. The covalent attachment of ubiquitin to a target protein proceeds through a multi-enzyme cascade. Initially, E1 activates ubiquitin and is then transferred to a cysteine residue of an E2 ubiquitin-conjugating enzyme (ubc). Finally, the E2 itself, or more commonly in concert with an E3 ubiquitin ligase, ligates the ubiquitin via its carboxy terminus to lysine residues of a protein substrate. This enzymatic cascade, responsible for ubiquitylating target proteins is complex, and its regulation is only beginning to be understood. The complexity stems from the large number of E2 and E3 enzymes; in humans, more than 30 E2s and hundreds of putative E3 ligases have been identified. The enzymatic nature, multitude of E2 and E3s and their specific substrate recognition predestines them as therapeutic targets in major diseases.. Targeting components of ubiquitination pathway for drug ...
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The split-ubiquitin system provides a method for overcoming this limitation.[11] In the split-ubiquitin system, two integral ... The reconstituted split-ubiquitin molecule is recognized by ubiquitin specific proteases, which cleave off the transcription ... a C-terminal ubiquitin moiety ("Cub", residues 35-76) and an N-terminal ubiquitin moiety ("Nub", residues 1-34). These fused ... Split-ubiquitin yeast two-hybrid[edit]. One limitation of classic yeast two-hybrid screens is that they are limited to soluble ...
"Ubiquitin Signalling". WEHI. 17 April 2019. "ACRF Centre for Therapeutic Target Discovery". Australian Cancer Research ... Ubiquitin Signalling (Professor David Komander) The institute is one of five research centres to establish the ACRF Centre for ...
The same enzyme that phosphorylates the CTD also phosphorylates the Rad6 complex,[58][59] which in turn adds a ubiquitin mark ... The type of modification (Me: methyl, P: phosphate, Ac: acetyl, Ub: ubiquitin) ... "Regulation of the ubiquitin-conjugating enzyme hHR6A by CDK-mediated phosphorylation". The EMBO Journal. 21 (8): 2009-18. doi ...
Interaction with CHIP (Carboxyl-terminus of Hsp70 Interacting Protein)-an E3 ubiquitin ligase-allows Hsp70 to pass proteins to ... Lüders J, Demand J, Höhfeld J (February 2000). "The ubiquitin-related BAG-1 provides a link between the molecular chaperones ...
ubiquitin protein ligase binding. • p53 binding. • SUMO transferase activity. • ubiquitin-protein transferase activity. • ... ubiquitin binding. Cellular component. • cytosol. • endocytic vesicle membrane. • plasma membrane. • synapse. • nuclear body. • ... Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by ... ubiquitin protein ligase activity. • NEDD8 ligase activity. • disordered domain specific binding. • protein domain specific ...
Raboy B, Sharon G, Parag HA, Shochat Y, Kulka RG (1991). "Effect of stress on protein degradation: role of the ubiquitin system ... The small 8-kilodalton protein ubiquitin, which marks proteins for degradation, also has features of a heat shock protein.[8] A ...
Prokaryotic ubiquitin-like protein. This article incorporates text from the United States National Library of Medicine, which ...
The MID1 E3 ubiquitin ligase activity is catalysed by the RING domain, a hallmark of one of the main classes of E3 ubiquitin ... Several MID1 E3 ubiquitin ligase targets have been reported: Alpha4 (α4) and its associated phosphatase, PP2A, Fu, Pax6 and ... MID1 is a microtubular protein that acts as an ubiquitin E3 ligase in vitro and in cells. Ubiquitination is a type of post- ... Napolitano LM, Jaffray EG, Hay RT, Meroni G (March 2011). "Functional interactions between ubiquitin E2 enzymes and TRIM ...
Ubiquitin-receptor proteins have an N-terminal ubiquitin-like (UBL) domain and one or more ubiquitin-associated (UBA) domains. ... It has been proposed that ubiquitin is the slowest-evolving protein identified to date.[53] Ubiquitin contains seven lysine ... In the first step, a ubiquitin-activating enzyme (known as E1) hydrolyzes ATP and adenylylates a ubiquitin molecule. This is ... Once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin ...
PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor populations. During later maturation stages, PDGF signalling has been implicated in tissue remodelling and cellular differentiation, and in inductive events involved in patterning and morphogenesis. In addition to driving mesenchymal proliferation, PDGFs have been shown to direct the migration, differentiation and function of a variety of specialised mesenchymal and migratory cell types, both during development and in the adult animal.[13][14][15] Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C)[16][17] which are active in angiogenesis and endothelial cell growth, and placenta growth factor (PlGF) which is also active in angiogenesis.[18] PDGF plays a role in embryonic development, cell proliferation, cell migration, and angiogenesis.[19] Over-expression of PDGF has been linked to several diseases such as ...
ubiquitin protein ligase binding. • cyclin binding. • cyclin-dependent protein kinase activating kinase activity. • cyclin- ... p21 is negatively regulated by ubiquitin ligases both over the course of the cell cycle and in response to DNA damage. ... Specifically, over the G1/S transition it has been demonstrated that the E3 ubiquitin ligase complex SCFSkp2 induces ... Bornstein, G.; Bloom, J.; Sitry-Shevah, D.; Nakayama, K.; Pagano, M.; Hershko, A. (2003). "Role of the SCFSkp2 Ubiquitin Ligase ...
Several proteins such as SNAI1/SNAIL,[58][59] ZFHX1B/SIP1,[60] SNAI2/SLUG,[61][62] TWIST1[63] and DeltaEF1[64] have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells.[58][59][60][61][63][64] Another group of genes, such as AML1, p300 and HNF3,[65] can upregulate the expression of E-cadherin.[66] In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with ...
RET is an abbreviation for "rearranged during transfection", as the DNA sequence of this gene was originally found to be rearranged within a 3T3 fibroblast cell line following its transfection with DNA taken from human lymphoma cells.[6] The human gene RET is localized to chromosome 10 (10q11.2) and contains 21 exons.[7] The natural alternative splicing of the RET gene results in the production of 3 different isoforms of the protein RET. RET51, RET43 and RET9 contain 51, 43 and 9 amino acids in their C-terminal tail respectively.[8] The biological roles of isoforms RET51 and RET9 are the most well studied in-vivo as these are the most common isoforms in which RET occurs. Common to each isoform is a domain structure. Each protein is divided into three domains: an N-terminal extracellular domain with four cadherin-like repeats and a cysteine-rich region, a hydrophobic transmembrane domain and a cytoplasmic tyrosine kinase domain, which is split by an insertion of 27 amino acids. Within the ...
Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. Electrons from FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S] and tunnel along the [Fe-S] relay until they reach the [3Fe-4S] iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full ...
... -nick contains binding domains for histone acetyltransferases and for ubiquitin ligases. ...
ubiquitin-proteasome: protein ubiquitin along with enzymes is key for the degradation of many proteins that cause ... The alpha-synuclein-ubiquitin complex cannot be directed to the proteasome. This protein accumulation forms proteinaceous ... brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin ...
Ubiquitin-like 1-activating enzyme E1B (UBLE1B) also known as SUMO-activating enzyme subunit 2 (SAE2) is an enzyme that in ... Ubiquitin tag has a well understood role of directing protein towards degradation by proteasome. The role SUMO molecules play ... "Entrez Gene: ubiquitin-like modifier activating enzyme 2". Retrieved 2011-08-30. Okuma T, Honda R, Ichikawa G, Tsumagari N, ... The predicted protein sequence is more analogous to yeast UBA2 (35% identity) than human UBA3 or E1 (in ubiquitin pathway). The ...
2005). Ubiquitin-Proteasome Protocols. Springer Science & Business Media. p. PA7. ISBN 9781592598953. Research In Technology Of ...
... (EC 3.4.19.12, ubiquitin C-terminal hydrolase, yeast ubiquitin hydrolase) is an enzyme. This enzyme ... Wilkinson, K.D.; Rawlings, N.D.; Woessner, J.F. (1998). "Ubiquitin C-terminal hydrolase". In Barrett, A.J. (ed.). Handbook of ... peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin This enzyme hydrolyses links to polypeptides smaller ...
Ub is then transferred to an E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ... the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome ... First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester bond and mobilises it in an ... Parkin is a 465-residue E3 ubiquitin ligase that plays a critical role in ubiquitination- the process whereby molecules are ...
... ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E2 ubiquitin- ... ubiquitin conjugating enzyme activity. • ubiquitin-protein transferase activity. • transferase activity. • protein binding. ... Ubiquitin-conjugating enzyme E2 E3 is a protein that in humans is encoded by the UBE2E3 gene.[5][6] ... "Ubiquitin charging of human class III ubiquitin-conjugating enzymes triggers their nuclear import". J. Cell Biol. 167 (4): 649- ...
In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with ubiquitin to select them for later ... Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G (November 1999). "Ubiquitin tag for sperm ...
This binding event allows the transferral of ubiquitin from E2 to a lysine residue on the target protein. The first hint that ... Different combinations of Cullin and FBPs can generate on the order of a hundred types of E3 ubiquitin ligases that target ... For instance, ubiquitin-mediated autocatalytic degradation of FBPs is a mechanism of decreasing SCF activity. Well- ... Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex that catalyzes the ...
The mechanism (or pathogenesis) of Kaufman oculocerebrofacial syndrome appears to begin due to a mutation in the E3 ubiquitin ... UBE3B). One finds that the normal mechanism of UBE3B gene is important in the ubiquitin-proteasome system. The aforementioned ... Nandi, Dipankar; Tahiliani, Pankaj; Kumar, Anujith; Chandu, Dilip (2006). "The ubiquitin-proteasome system" (PDF). Journal of ... Furthermore the following are treatment options: Thyroid hormone replacement Speech therapy Hearing aids Ubiquitin "Kaufman ...
Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo. The egg cell ... "Ubiquitin tag for sperm mitochondria". Nature. 402 (6760): 371-372. Bibcode:1999Natur.402..371S. doi:10.1038/46466. PMID ...
Small ubiquitin-related modifier needs to be associated with it before it can be localized at the nuclear pore. RANGAP1 has ... All in the ubiquitin family". Science. 289 (5479): 563-4. doi:10.1126/science.289.5479.563. PMID 10939967. Hillig RC, Renault L ... Mahajan R, Delphin C, Guan T, Gerace L, Melchior F (1997). "A small ubiquitin-related polypeptide involved in targeting RanGAP1 ... Matunis MJ, Coutavas E, Blobel G (1997). "A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase- ...
The regulation could be related to ubiquitin function; proteins with ubiquitination type function were found to interact with ... Dhananjayan SC, Ismail A, Nawaz Z (2005). "Ubiquitin and control of transcription". Essays Biochem. 41: 69-80. doi:10.1042/ ... that is a metalloprotease component of 26S proteasome that also degrades proteins targeted for destruction by the ubiquitin ...
Nandi D, Tahiliani P, Kumar A, Chandu D (March 2006). "The ubiquitin-proteasome system" (PDF). J. Biosci. 31 (1): 137-55. doi: ... a ubiquitin tag) and feed them into the proteolytic cavity. Another large class of protein compartments are bacterial ...
In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with ubiquitin to select them for later ... ISBN 978-0-306-47754-6. Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G (November 1999). "Ubiquitin ...
His laboratory has played a central role in elucidating the role of a family of enzymes, the cullin-RING ubiquitin ligases ( ... Petroski, Matthew D.; Deshaies, Raymond J. (January 2005). "Function and regulation of cullin-RING ubiquitin ligases". Nature ... Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele (December 2014). "SCF ubiquitin ligase-targeted therapies". Nature Reviews ... Cardozo, Timothy; Pagano, Michele (September 2004). "The SCF ubiquitin ligase: insights into a molecular machine". Nature ...
Courseware Index, ,Year 3, ,Ubiquitin Index, ,Ubiquitin Pathway,. 3.0 Enzymes of the Ubiquitin Pathway. 3.1 Ubiquitin- ... E3s which do form thiol esters with ubiquitin. The tumour supressor p53 is targeted for ubiquitin-mediated degradation ... E1 is also found to form complexes with ubiquitin conjugating enzymes and E3s [17].. 3.2 Ubiquitin-conjugating enzymes. While ... Until recently the proximal donor of ubiquitin to target proteins was thought to a ubiquitin charged E2 (UBC), and E3s were not ...
Ubiquitin ligase. References[edit]. *^ Nandi D, Tahiliani P, Kumar A, Chandu D (2006). "The ubiquitin-proteasome system". ... Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step ... A ubiquitin-activating enzyme, or E1, first activates the ubiquitin by covalently attaching the molecule to its active site ... Once conjugated to ubiquitin, the E2 molecule binds one of several ubiquitin ligases or E3s via a structurally conserved ...
The ubiquitin system.. Hershko A1, Ciechanover A.. Author information. 1. Unit of Biochemistry, Faculty of Medicine, Technion- ... The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ... Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including ... The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this ...
Ubiquitin is a small protein that is found in almost all cellular tissues in humans and other eukaryotic organisms, which helps ... Ligation with ubiquitin ligases (E3s). Through these steps, the ubiquitin molecule forms an isopeptide bond with the residue of ... Ubiquitin-like modifiers may produce similar results to ubiquitin although in some cases they can be distinctly different. For ... This can occur with the attachment of a single ubiquitin protein, which is known as monoubiquitination, or several ubiquitin ...
A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific ... Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin- ... Deubiquitination of NF-κB by ubiquitin-specific protease-7 promotes transcription. PNAS. 2013;110:618-23.CrossRefGoogle Scholar ... This necessity for the major part has been found to be taken care of by the ubiquitin-proteasome system (UPS). The system was ...
... or with a lysine in another ubiquitin molecule to form a ubiquitin chain that attaches itself to a target protein. Ubiquitin ... Ubiquitin conserved site (IPR019954). Short name: Ubiquitin_CS Description. Ubiquitinylation is an ATP-dependent process that ... a ubiquitin-conjugating enzyme (E2, IPR000608), and a ubiquitin ligase (E3, IPR000569, IPR003613), which work sequentially in a ... Ubiquitin is a protein of 76 amino acid residues, found in all eukaryotic cells and whose sequence is extremely well conserved ...
... of the last ubiquitin of a growing chain and the C terminus of a new ubiquitin. The fate of a polyubiquitin-tagged protein ... the ubiquitin tag consists of a chain of ubiquitin domains (polyubiquitin), which is formed by linkages between an exposed ... Specifically, here we investigate the response of ubiquitin to constant stretching forces and acting on the C and N termini, ... Ubiquitin is significantly larger than these peptides. However, our present work focuses on unfolding, which is easier to ...
InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource, capitalising on their individual strengths to produce a powerful integrated database and diagnostic tool.
The ubiquitin 26S proteasome proteolytic pathway.. Smalle J1, Vierstra RD.. Author information. 1. Department of Genetics, 445 ... One important proteolytic pathway involves the small protein ubiquitin (Ub) and the 26S proteasome, a 2-MDa protease complex. ...
Ubiquitin-conjugating enzyme E2 D3. A. 147. Homo sapiens. Mutation(s): 1 Gene Names: UBC5C, UBCH5C, UBE2D2, UBE2D3. EC: 6.3. ... Structural insights into the conformation and oligomerization of E2~ubiquitin conjugates.. Page, R.C., Pruneda, J.N., Amick, J. ... The E2~Ub conjugate interacts with a ubiquitin ligase (E3) to transfer Ub to a lysine residue on a target protein. The flexibly ... Post-translational modification of proteins by ubiquitin (Ub) regulates a host of cellular processes, including protein quality ...
If you know of any papers that use this antibody, please contact us at antibodies [at] alzforum [dot] org for consideration in the References section.. ...
This effect was suppressed by overexpressing ubiquitin and also by directly fusing ubiquitin to the C terminus of Gag, the ... ubiquitin;. RSV,. Rous sarcoma virus;. L domain,. late domain;. GFP,. green fluorescent protein;. AP,. adaptor protein. ... Ubiquitin (Ub) is a 76-aa protein present in cells either as a free molecule or covalently attached to lysines in a wide ... Ubiquitin is part of the retrovirus budding machinery. Akash Patnaik, Vincent Chau, and John W. Wills ...
Proteins can specifically bind to ubiquitin via ubiquitin-binding domains (UBDs). The distances between individual ubiquitin ... Ubiquitination requires three types of enzyme: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ... ubiquitin fold-modifier-1 (UFM1) and ubiquitin-like protein-5 (UBL5, which is but known as homologous to ubiquitin-1 [Hub1] in ... that of ubiquitin. Known UBLs include: small ubiquitin-like modifier (SUMO), ubiquitin cross-reactive protein (UCRP, also known ...
E1 - the ubiquitin activating enzyme E1 (1) Ubiquitin-C-O + ATP ----, P-P + Ubiquitin-C~AMP " " O O (carbonyl from the C-term ( ... Ubiquitin-C~S-E1 " " O O (thioester) E2 - ubiquitin carrier protein (3) E2-SH + Ubiqutin-C~S-E1 ----, E1-SH + Ubiquitin-C~S-E2 ... Ubiquitin itself has exposed surface lysines which can be tagged, sometimes leading to chains of ubiquitin attached to a target ... ubiquitin (thing). See all of ubiquitin, no other writeups in this node. ...
Ubiquitin-conjugating enzyme E2 L3. C, D. 156. Homo sapiens. Mutation(s): 1 Gene Names: UBE2L3, UBCE7, UBCH7. EC: 2.3.2.23. ... E3 ubiquitin-protein ligase ARIH1. A, B. 470. Homo sapiens. Mutation(s): 0 Gene Names: ARIH1, ARI, MOP6, UBCH7BP, HUSSY-27. EC ... Ubiquitin C variant. E. 82. Homo sapiens. Mutation(s): 0 Gene Names: UBC. ... Both types of E3 bind E2∼ubiquitin (E2∼Ub) via their RINGs but canonical RING E3s promote closed E2∼Ub conformat ... ...
Enabling and supporting ubiquitin system targeted drug discovery Jason Brown, Ubiquigent. 16:00. Ubiquitin -Omics for Target ... Ubiquitin system modulation: strategies and technologies Satpal Virdee, University of Dundee. 12:00. Chemical Ubiquitination ... Inhibitors of the E2 ubiquitin conjugating enzyme Rad6: discovery and anticancer properties Andrew Westwell, Cardiff University ... Protein turnover is crucial in maintaining cellular homeostasis and this process is largely controlled by the Ubiquitin ...
Free ubiquitinUniRule annotation. ,p>Information which has been generated by the UniProtKB automatic annotation system, without ... Free ubiquitinUniRule annotation. ,p>Information which has been generated by the UniProtKB automatic annotation system, without ... Free ubiquitinUniRule annotation. ,p>Information which has been generated by the UniProtKB automatic annotation system, without ... Free ubiquitinUniRule annotation. ,p>Information which has been generated by the UniProtKB automatic annotation system, without ...
Ubiquitin is a universal modifier used by eukaryotes to tag proteins for degradation. Now Pearce et al. (see the Perspective by ... M. J. Pearce, J. Mintseris, J. Ferreyra, S. P. Gygi, K. H. Darwin, Ubiquitin-like protein involved in the proteasome pathway of ... A prokaryotic version of ubiquitin, a eukaryotic tag for protein degradation, is linked to lysines in prokaryotic proteins ... A prokaryotic version of ubiquitin, a eukaryotic tag for protein degradation, is linked to lysines in prokaryotic proteins ...
Two groups report that the E3 ubiquitin ligase Nedd4 contributes to both dendritic (Kawabe et al.) and axonal (Drinjakovic et ... examined the role of the ubiquitin-proteasome system in axonal branching of retinal ganglion cells (RGCs). Electroporation of a ... The E3 ubiquitin ligase Nedd4 contributes to both dendritic and axonal branching. ... The E3 ubiquitin ligase Nedd4 contributes to both dendritic and axonal branching. ...
Purchase Ubiquitin and Ubiquitin-like Protein Modifiers, Volume 618 - 1st Edition. Print Book & E-Book. ISBN 9780128163597, ... Ubiquitin and Ubiquitin-like Protein Modifiers, Volume 618 1st Edition. 0.0 star rating Write a review ... Methods to measure ubiquitin chain length and linkage, Genetic approaches to study the yeast ubiquitin system, Enzymatic ... 5. Methods to measure ubiquitin chain length and linkage. Fumiaki Ohtake, Hikaru Tsuchiya, Keiji Tanaka and Yasushi Saeki. 6. ...
Ubiquitin is a protein that in humans is encoded by the UBB gene. Ubiquitin is one of the most conserved proteins known in ... Ubiquitin is covalently bound to proteins to be degraded, and presumably labels these proteins for degradation. Ubiquitin also ... "Entrez Gene: UBB ubiquitin B". Conaway RC, Brower CS, Conaway JW (2002). "Emerging roles of ubiquitin in transcription ... 1985). "The human ubiquitin multigene family: some genes contain multiple directly repeated ubiquitin coding sequences". EMBO J ...
Modification of proteins with ubiquitin or ubiquitin-like proteins (UBLs) by means of an E1-E2-E3 cascade controls many ... which specifically activates ubiquitin but not other ubiquitin-like proteins in vitro and in vivo. Human Uba6 and Ube1 have ... Ubiquitin conjugation involves adenylation and thioesterification of the carboxy-terminal carboxylate of ubiquitin by the E1- ... It is currently thought that Ube1/Uba1 is the sole E1 for charging of E2s with ubiquitin in animals and fungi1,8. Here we ...
found that ubiquitin-specific protease 14 could be a potential therapeutic target for oral squamous cell carcinoma patients. [ ... Ubiquitin. Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer. 12 , Sep ... Ubiquitin-specific protease 14 regulates cell proliferation and apoptosis in oral squamous cell carcinoma. 464 , Jul 06 2018 ... Protein are recognized for destruction due to the actions of the Ubiquitin protein kinases. [Read the Full Post] ...
Ubiquitin Signaling (A8). Scientific Organizers: David Komander and Sylvie Urbé. January 28-February 1, 2018. Granlibakken ...
The HaloTag®-Ubiquitin Fusion Vector contains the coding region for an N-terminal HaloTag® fusion to the ubiquitin protein ( ... The majority of proteins and their abundance are regulated via the ubiquitin proteasome system (UPS), which uses ubiquitin ... Create target-specific live-cell ubiquitin assays that globally measure all types of ubiquitination on a target protein. ... Fusion Vectors for the NanoBRET™ Ubiquitin Proteasome System Interaction Assays. *Measure induced interaction between target ...
A ubiquitin-conjugating enzyme that regulates the cell cycle promotes chromosome missegregation and tumor formation, according ... Ubiquitin-conjugating enzyme promotes chromosome missegregation and tumor formation. *Download PDF Copy ... A ubiquitin-conjugating enzyme that regulates the cell cycle promotes chromosome missegregation and tumor formation, according ...
D. O. V. Alonso and V. Daggett, "Molecular dynamics simulations of hydrophobic collapse of ubiquitin," Protein Science, vol. 7 ... E. Segev, T. Wyttenbach, M. T. Bowers, and R. B. Gerber, "Conformational evolution of ubiquitin ions in electrospray mass ... Water Evaporation and Conformational Changes from Partially Solvated Ubiquitin. Saravana Prakash Thirumuruganandham and Herbert ... "Transfer of structural elements from compact to extended states in unsolvated ubiquitin," Journal of the American Chemical ...
1985 Ubiquitin carboxyl-terminal hydrolase acts on ubiquitin carboxyl-terminal amides. J. Biol. Chem. 260: 7903-7910. ... There are two classes of Dub enzymes, the Ubp family (ubiquitin-specific proteases) and the Uch family (ubiquitin ... ubiquitin-conjugating (E2), and ubiquitin-ligating (E3) enzymes. A large number of E2 enzymes provide substrate specificity ... Ubiquitin is covalently ligated to target proteins by a multienzymatic system consisting of ubiquitin-activating (E1), ...
The evolutionarily conserved cullin family proteins can assemble as many as 400 distinct E3 ubiquitin ligase complexes that ... CRL4s: the CUL4-RING E3 ubiquitin ligases Trends Biochem Sci. 2009 Nov;34(11):562-70. doi: 10.1016/j.tibs.2009.07.002. Epub ... The evolutionarily conserved cullin family proteins can assemble as many as 400 distinct E3 ubiquitin ligase complexes that ...
... ,Proteolytic degradation is critical to the maintenance of appropriate levels ... Ubiquitin/Proteasome Fraction II Extract from GeneTex. 2. Ubiquitin Fraction I Extract from GeneTex. 3. Mouse Anti-Ubiquitin, ... EP-500 contains ubiquitin, ubiquitin conjugating enzymes (E2s), and ubiquitin ligases (E3s). EP-500 is ideal for demonstrating ... Ubiquitin Related I Sampler Kit from BD Biosciences Pharmingen. 5. Rabbit Anti-Human Ubiquitin-conjugating enzyme E2N ...
  • In vitro these enzymes are very poor at transferring ubiquitin to proteins on their own, and probably require an E3 to aid this in vivo . (nottingham.ac.uk)
  • It has been suggested that such motifs be called "degrons", degrons being any motif that targets proteins for degradation (by the ubiquitin-dependent or and other systems). (nottingham.ac.uk)
  • Until recently the proximal donor of ubiquitin to target proteins was thought to a ubiquitin charged E2 (UBC), and E3s were not thought to be directly involved in the transfer of ubiquitin to the substrate protein. (nottingham.ac.uk)
  • The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. (nih.gov)
  • In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. (nih.gov)
  • Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. (nih.gov)
  • Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems. (nih.gov)
  • Ubiquitin is a small protein that is found in almost all cellular tissues in humans and other eukaryotic organisms, which helps to regulate the processes of other proteins in the body. (news-medical.net)
  • This can occur with the attachment of a single ubiquitin protein, which is known as monoubiquitination, or several ubiquitin proteins forming a chain, known as polyubiquitination. (news-medical.net)
  • There is an entirely family of proteins that interact with proteins in a similar way, which is referred to as ubiquitin-like modifiers. (news-medical.net)
  • The UPS in its most simplified form consists of a tagging factor in the form of the small protein ubiquitin, enzymes that mediate the tagging of unwanted or damaged proteins, and the proteasome, a large molecular shredder that cleaves tagged proteins in to smaller peptides for use in other anabolic processes. (springer.com)
  • Ubiquitin acts through its post-translational attachment (ubiquitinylation) to other proteins, where these modifications alter the function, location or trafficking of the protein, or targets it for destruction by the 26S proteasome [ PMID: 15454246 ]. (ebi.ac.uk)
  • U-box proteins as a new family of ubiquitin ligases. (ebi.ac.uk)
  • T he 76-residue protein ubiquitin fulfills many important regulatory functions in eukaryotic cells through its covalent attachment to other proteins ( 1 , 2 ). (pnas.org)
  • Post-translational modification of proteins by ubiquitin (Ub) regulates a host of cellular processes, including protein quality control, DNA repair, endocytosis, and cellular signaling. (rcsb.org)
  • Ubiquitin (Ub) is a 76-aa protein present in cells either as a free molecule or covalently attached to lysines in a wide variety of proteins. (pnas.org)
  • Ubiquitin ligates to proteins, committing them to the degradation pathway. (everything2.com)
  • Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal). (uniprot.org)
  • Ubiquitin is a universal modifier used by eukaryotes to tag proteins for degradation. (sciencemag.org)
  • A prokaryotic version of ubiquitin, a eukaryotic tag for protein degradation, is linked to lysines in prokaryotic proteins destined for destruction, a process called pupylation. (sciencemag.org)
  • Pickart, C. M. & Rose, I. A. Functional heterogeneity of ubiquitin carrier proteins. (nature.com)
  • The discovery that ubiquitin chains target proteins to the proteasome, which degrades and recycles proteins, was honored with the Nobel Prize in Chemistry in 2004. (wikipedia.org)
  • UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. (wikipedia.org)
  • Ubiquitin is covalently ligated to target proteins by a multienzymatic system consisting of ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin-ligating (E3) enzymes. (genetics.org)
  • The 19S particle is the regulatory unit and consists of a polyubiquitin recognition site, ATPases that provide energy for un-folding proteins, and a deubiquitinating enzyme that recycles ubiquitin. (genetics.org)
  • The evolutionarily conserved cullin family proteins can assemble as many as 400 distinct E3 ubiquitin ligase complexes that regulate diverse cellular pathways. (nih.gov)
  • The ubiquitin-proteasome pathway deconstructs most proteins in the eukaryotic cell cytosol and nucleus. (bio-medicine.org)
  • An enzymatic cascade is responsible for the attachment of multiple ubiquitin molecules to lysine residues of proteins targeted for degradation. (bio-medicine.org)
  • 10) Clearing misfolded mutant protein and inhibiting aggregate formation Decreasing mutant protein levels may also be achieved by enhancing polyQ protein clearance, through upregulation of the two main cellular pathways responsible for degradation of misfolded proteins--the ubiquitin-proteasome system (UPS) and autophagy. (acronymfinder.com)
  • The ubiquitin-proteasome system mediates protein recycling by tagging abnormal or unwanted proteins within cells with the small protein ubiquitin. (acronymfinder.com)
  • Ubiquitin is one of the most conserved proteins known in eukaryotic organisms. (wikipedia.org)
  • Ubiquitin is required for ATP-dependent, non-lysosomal intracellular protein degradation of abnormal proteins and normal proteins with a rapid turnover. (wikipedia.org)
  • Ubiquitin is covalently bound to proteins to be degraded, and presumably labels these proteins for degradation. (wikipedia.org)
  • SCF complexes physically link substrate proteins to the E2 ubiquitin-conjugating enzyme Cdc34, which catalyses substrate ubiquitination, leading to subsequent degradation by the 26S proteasome. (nih.gov)
  • Ubiquitin ligase trapping identifies an SCF(Saf1) pathway targeting unprocessed vacuolar/lysosomal proteins. (yeastgenome.org)
  • The ubiquitin-proteasome system (UPS) is the primary means by which cellular proteins are degraded and is a highly regulated system for elimination of misfolded or damaged proteins as well as proteins whose activity is acutely regulated by signaling pathways. (cellsignal.com)
  • Ubiquitin is a highly conserved 76-amino acid protein that can be covalently linked to many cellular proteins by the ubiquitination process. (cellsignal.com)
  • When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). (abcam.com)
  • Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. (abcam.com)
  • containing proteins bind poly-ubiquitin chains linked through Lys48 or Lys63 of ubiquitin. (cellsignal.com)
  • The addition of ubiquitin to proteins being degraded is performed by a reaction cascade consisting of three enzymes, named E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme), and E3 (ubiquitin ligase). (genome.jp)
  • Researchers at TMIMS have revealed that PINK1 (a serine/threonine kinase) and Parkin (a ubiquitin ligating enzyme: E3) work together to ubiquitylate the outer membrane proteins of damaged mitochondria to induce selective autophagy called mitophagy. (eurekalert.org)
  • It has been suggested that autophagy-adaptor proteins, which bind to both the ubiquitin and factors for autophagosome formation, are involved in a selective autophagy. (eurekalert.org)
  • Therefore, the researchers examined whether LC3 family proteins accumulate in the foci formed by the autophagy adaptor and ubiquitin. (eurekalert.org)
  • Yamano and colleagues then searched for the autophagy-related proteins (ATG proteins) that cooperates with OPTN and ubiquitin. (eurekalert.org)
  • Ubiquitin attaches to proteins, tagging them for disposal. (healthline.com)
  • Both ubiquitin and SUMO are used by cells to modify proteins post-translationally. (alzforum.org)
  • Apg7 activates two different ubiquitin-like proteins, Apg12 (ref. 10) and Apg8, and assigns them to specific E2 enzymes, Apg10 (ref. 11) and Apg3, respectively. (sigmaaldrich.com)
  • Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine repeat and a folding mutant of cystic fibrosis transmembrane conductance regulator, caused nearly complete inhibition of the ubiquitin-proteasome system. (sciencemag.org)
  • The ubiquitin-proteasome system (UPS) functions in cellular quality control by degrading misfolded, unassembled, or damaged proteins that could otherwise form potentially toxic aggregates ( 1 ). (sciencemag.org)
  • Because multiubiquitylated proteins are usually efficiently degraded by cellular proteasomes, the presence of elevated ubiquitin conjugates associated with intracellular deposits of aggregated protein in diseased neurons in nearly all sporadic and hereditary neurodegenerative diseases has long suggested a linkage between UPS dysfunction and pathogenesis ( 2 ). (sciencemag.org)
  • Ubiquitinated proteins with attached ubiquitin units have altered functions and are marked for degradation. (biocompare.com)
  • Callis J, Raasch JA, Vierstra RD (1990) Ubiquitin extension proteins of Arabidopsis thaliana. (springer.com)
  • These data suggest that ZNRF proteins play a role in the establishment and maintenance of neuronal transmission and plasticity via their ubiquitin ligase activity. (jneurosci.org)
  • The conjugation of ubiquitin to proteins at lysine residues (ubiquitination), thereby targeting them to the proteosome, is essential for the degradation of many proteins in eukaryotic cells. (jneurosci.org)
  • however, few E3 ubiquitin ligases that target membrane proteins (e.g. (jneurosci.org)
  • Ubiquitination is a post-translational modification in which one or more 76 amino acid polypeptide ubiquitin molecules are covalently linked to the lysine residues of target proteins. (frontiersin.org)
  • Ubiquitin, a highly conserved protein that has a major role in targeting cellular proteins for degradation by the 26S proteosome, is synthesized as a precursor protein consisting of either polyubiquitin chains or a single ubiquitin fused to an unrelated protein. (thermofisher.com)
  • Eukaryotes contain a highly conserved multi-enzyme system that covalently links ubiquitin to a variety of intracellular proteins that bear degradation signals recognized by this system. (caltech.edu)
  • USP15 cleaves the isopeptide bonds of polyubiquitin chains, and can cleave linear ubiquitin fusion proteins (Baker et al. (atlasgeneticsoncology.org)
  • The PHR proteins act as E3 ubiquitin ligases for the dual-leucine-zipper-bearing MAP kinase kinase kinase (DLK MAPKKK) to regulate the signal transduction cascade. (genetics.org)
  • These studies reveal that a major function of PHR proteins is to act as ubiquitin E3 ligases ( J in and G arner 2008 ). (genetics.org)
  • Previous studies have shown that HECT domain containing proteins are ubiquitin E3 ligases that play an important role in protein degradation. (ahajournals.org)
  • The generation of these epitopes requires the degradation and processing of proteins by the ubiquitin proteasome system (UPS). (hu-berlin.de)
  • Post-translational modification of proteins by SUMOs (small ubiquitin-related modifiers) plays an important role in a wide variety of biological processes. (portlandpress.com)
  • The ubiquitin-proteasome pathway (UPP) is the primary cytosolic proteolytic machinery for the selective degradation of various forms of damaged proteins. (biovision.com)
  • Proteins tagged by ubiquitination (e.g., attachment of ubiquitin to the target molecule) are degraded in the proteasome, a complex intracellular structure composed of multiple enzymatic complexes, presiding over protein catabolism. (biovision.com)
  • Once conjugated to ubiquitin, the E2 molecule binds one of several ubiquitin ligases or E3s via a structurally conserved binding region. (wikipedia.org)
  • There are many different E3 ligases, which are responsible for the type of ubiquitin chain formed, the specificity of the target protein, and the regulation of the ubiquitinylation process [ PMID: 12646216 ]. (ebi.ac.uk)
  • EP-500 contains ubiquitin, ubiquitin conjugating enzymes (E2s), and ubiquitin ligases (E3s). (bio-medicine.org)
  • Many key activators and inhibitors of cell division are targeted for degradation by a recently described family of E3 ubiquitin protein ligases termed Skp1-Cdc53-F-box protein (SCF) complexes. (nih.gov)
  • Petroski MD and Deshaies RJ (2005) Function and regulation of cullin-RING ubiquitin ligases. (yeastgenome.org)
  • A hitchhiker's guide to the cullin ubiquitin ligases: SCF and its kin. (yeastgenome.org)
  • Cullin/RING ubiquitin ligases (CRL) comprise the largest subfamily of ubiquitin ligases. (frontiersin.org)
  • In this review, we will discuss the regulation of CRL ubiquitin ligases and their roles in control of the DDR. (frontiersin.org)
  • Thus far, more than 600 ubiquitin ligases have been identified in the human genome, although many of them have not been linked to any substrates or biological activities. (frontiersin.org)
  • Based on their domain characteristics, ubiquitin ligases can be separated into two sub-groups, HECT domain E3 ligases and RING finger domain E3 ligases ( Pickart, 2004 ). (frontiersin.org)
  • Hundreds of ubiquitin ligases and hydrolases have been identified, implicating ubiquitin as a major regulatory element in many crucial cellular systems. (phosphosite.org)
  • Here we describe the identification of a closely related protein, ZNRF2, thus defining a novel family of ZNRF E3 ubiquitin ligases. (jneurosci.org)
  • E3 ubiquitin ligases. (proteopedia.org)
  • The role of ubiquitin-protein ligases in neurodegenerative disease. (proteopedia.org)
  • It then transfers the activated ubiquitin to one of the UBIQUITIN-PROTEIN LIGASES. (harvard.edu)
  • A SUMO-binding motif in Ubc9 (ubiquitin-conjugating enzyme 9) contributes to SUMO chain formation in vitro and SUMO E3 ligases further enhance SUMO polymerization. (portlandpress.com)
  • Ubiquitin-conjugating enzymes , also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes , perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome . (wikipedia.org)
  • For example, one member of this family called SUMO can bind to a protein "tagged" by ubiquitin for degradation, stabilizing it and preventing it from being sent to the proteasome. (news-medical.net)
  • Canning M, Boutell C, Parkinson J, Everett RD. A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7. (springer.com)
  • It appears that Lys(11)-, Lys(29) and Lys(48)-linked poly-ubiquitin chains target the protein to the proteasome for degradation, while mono-ubiquitinylated and Lys(6)- or Lys(63)-linked poly-ubiquitin chains signal reversible modifications in protein activity, location or trafficking [ PMID: 14998368 ]. (ebi.ac.uk)
  • The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. (ebi.ac.uk)
  • The pathway consists of an enzymatic cascade that links the polypeptide cofactor Ubiquitin to specific protein targets, which mark them for degradation by the proteasome. (soci.org)
  • This interaction promoted the ubiquitylation of Rap2A, which ubiquitin-linkage specific antibodies indicated was the K63-linked mono- or di-ubiquitin involved in regulation, not proteasome-mediated degradation. (sciencemag.org)
  • Ciechanover, A., Finley, D. & Varshavsky, A. Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. (nature.com)
  • It has been suggested that deubiquitination enzymes, like the ubiquitin-conjugating enzymes, have diverse roles in regulation of protein degradation or modification. (genetics.org)
  • Positive regulation occurs when polyubiquitin chains are cleaved to produce free ubiquitin groups that are then available for attachment to new substrates targeted for degradation. (genetics.org)
  • His career has focused on investigating the cellular machinery that mediates protein degradation by the Ubiquitin-Proteasome System (UPS), and how this machinery regulates cell division. (acronymfinder.com)
  • Ubiquitin also binds to histone H2A in actively transcribed regions but does not cause histone H2A degradation, suggesting that ubiquitin is also involved in regulation of gene expression. (wikipedia.org)
  • The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. (nature.com)
  • Song, B.L., Sever, N. & DeBose-Boyd, R.A. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. (nature.com)
  • Shen, Y., Ballar, P. & Fang, S. Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of α-1-antitrypsin. (nature.com)
  • AAA ATPase p97/valosin-containing protein interacts with gp78, a ubiquitin ligase for endoplasmic reticulum-associated degradation. (nature.com)
  • The concepts of SCF ubiquitin ligase function are illustrated by analysis of the degradation pathway for the G1 cyclin Cln2. (nih.gov)
  • In 2004, the Nobel Prize in Chemistry was awarded to Aaron Ciechanover, Avram Hershko, and Irwin Rose for the discovery of this process, called ubiquitin mediated degradation (proteolysis). (healthline.com)
  • Here, we focus on recent progress centered on the mechanisms regulating ubiquitination of histone modifying enzymes, including ubiquitin proteasomal degradation and the reverse process of deubiquitination. (mdpi.com)
  • Siah1 is an E3 ubiquitin ligase that contributes to proteasome-mediated degradation of multiple targets in key cellular processes and which shows promise as a therapeutic target in oncology. (iucr.org)
  • Background - The ubiquitin-proteasome system is the major intracellular protein degradation pathway in eucaryotic cells. (ahajournals.org)
  • HLI 373 is an inhibitor of Hdm2 ubiquitin ligase (E3) which blocks Hdm2-mediated ubiquitylation, proteasomal degradation of p53 and activates p53-dependent transcription. (adooq.com)
  • Hydrogen peroxide mediates the apoptotic effect of cisplatin by downregulating bcl-2 through ubiquitin-proteasomal degradation. (cdc.gov)
  • Bcl-2 was downregulated by cisplatin treatment through ubiquitin-proteasomal degradation which was mediated by ROS. (cdc.gov)
  • The first step in ubiquitinylation involves activation of ubiquitin , followed by transfer to a ubiquitin conjugating enzyme. (nottingham.ac.uk)
  • A ubiquitin-activating enzyme , or E1, first activates the ubiquitin by covalently attaching the molecule to its active site cysteine residue. (wikipedia.org)
  • Hu M, Li P, Li M, Li W, Yao T, Wu J-W, Gu W, Cohen RE, Shi Y. Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. (springer.com)
  • Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1, IPR000011 ), a ubiquitin-conjugating enzyme (E2, IPR000608 ), and a ubiquitin ligase (E3, IPR000569 , IPR003613 ), which work sequentially in a cascade. (ebi.ac.uk)
  • In the ubiquitination cascade, a thioester-linked conjugate between the C-terminus of Ub and the active site cysteine of a ubiquitin-conjugating enzyme (E2) is formed. (rcsb.org)
  • Finley, D., Ciechanover, A. & Varshavsky, A. Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85. (nature.com)
  • Ubp3 is a deubiquitination enzyme and a member of a large family of cysteine proteases that cleave ubiquitin moieties from protein substrates. (genetics.org)
  • A "ubiquitin activating enzyme" (E1) forms a thio-ester bond with ubiquitin. (cellsignal.com)
  • This reaction allows subsequent binding of ubiquitin to a "ubiquitin conjugating enzyme" (E2), followed by the formation of an isopeptide bond between the carboxy-terminus of ubiquitin and the ε-amino group of a lysine residue on the substrate protein. (cellsignal.com)
  • Ubiquitination is controlled by a multi-enzyme cascade that involves E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin-ligating enzyme) activities ( Pickart, 2001 ). (jneurosci.org)
  • In this study, two new ExoU orthologs were identified and the ubiquitin activation of the rickettsial enzyme RP534 was verified. (asm.org)
  • The ubiquitination reaction is initiated when ubiquitin is activated by the ubiquitin-activating enzyme, E1. (frontiersin.org)
  • Following ubiquitin activation, activated ubiquitin is transferred to a ubiquitin-conjugating enzyme, E2 (also known as Ubc), in another ATP-dependent reaction. (frontiersin.org)
  • Ubiquitin-protein ligase (UPL) ( E3 ) or E3 ubiquitin-protein ligase in combination with ubiquitin-conjugating enzyme (E2) causes the attachment of ubiquitin to lysine in a target protein [1] . (proteopedia.org)
  • Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1). (sigmaaldrich.com)
  • Currently, only a few classes of compounds have been discovered to inhibit the ubiquitin-activating enzyme (E1) and only one class is relatively selective in E1 inhibition in cells. (sigmaaldrich.com)
  • The inhibitory activity of these small molecules on ubiquitin conjugation has been traced to their inhibition of the ubiquitin E1 enzyme. (sigmaaldrich.com)
  • By characterizing additional genetic suppressors of rpm-1 , we present here a new member of the DLK-1 pathway, UEV-3 , an E2 ubiquitin-conjugating enzyme variant. (genetics.org)
  • These mutations affect the gene uev-3 , a ubiquitin E2 conjugating (UBC) enzyme variant (UEV). (genetics.org)
  • Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways. (mdpi.com)
  • Dong M, Pang X, Xu Y, Wen F, Zhang Y. Ubiquitin-Conjugating Enzyme 9 Promotes Epithelial Ovarian Cancer Cell Proliferation in Vitro . (mdpi.com)
  • The ubiquitin-proteasome pathway in Parkinson's disease and other neurodegenerative diseases. (ebi.ac.uk)
  • The ubiquitin 26S proteasome proteolytic pathway. (nih.gov)
  • One important proteolytic pathway involves the small protein ubiquitin (Ub) and the 26S proteasome, a 2-MDa protease complex. (nih.gov)
  • Protein turnover is crucial in maintaining cellular homeostasis and this process is largely controlled by the Ubiquitin Proteasome Pathway (UPP). (soci.org)
  • The basic functions of ubiquitin and the components of the ubiquitylation pathway were elucidated in the early 1980s at the Technion by Aaron Ciechanover, Avram Hershko, and Irwin Rose for which the Nobel Prize in Chemistry was awarded in 2004. (wikipedia.org)
  • Several genetic diseases are associated with defects in the ubiquitin-proteasome pathway. (bio-medicine.org)
  • GA signaling controls seed germination in the sly1 mutant background, in which DELLA repressors cannot be destroyed by the ubiquitin-proteasome pathway. (plantphysiol.org)
  • therefore, it is not surprising that viruses connect to the ubiquitin pathway at many levels. (mit.edu)
  • Here, we review current knowledge of how the ubiquitin pathway alters viral replication and how viruses influence the ubiquitin pathway to enhance their own replication. (mit.edu)
  • The critical role that the Ubiquitin Proteasome Pathway (UPP) plays in cellular signaling coupled with increasing validation of the therapeutic potential of targets in this pathway is accelerating interest in this field among both academic and pharmaceutical researchers. (biovision.com)
  • BioVision is pleased to offer a variety of reagents to the researchers doing research in the Ubiquitin Proteasome Pathway. (biovision.com)
  • The ubiquitination process covalently attaches ubiquitin , a short protein of 76 amino acids , to a lysine residue on the target protein. (wikipedia.org)
  • Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP -dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell . (wikipedia.org)
  • Through a process known as ubiquitination or ubiquitylation, an ubiquitin molecule can bind to a substrate protein, changing the way it functions. (news-medical.net)
  • Ubiquitination occurs when an ubiquitin molecule bonds to a substrate protein and is a type of post-translational modification. (news-medical.net)
  • The addition of ubiquitin to a substrate protein is called ubiquitylation (or, alternatively, ubiquitination or ubiquitinylation). (wikipedia.org)
  • Ubiquitylation (also known as ubiquitination or ubiquitinylation) is an enzymatic post-translational modification in which a ubiquitin protein is attached to a substrate protein. (wikipedia.org)
  • Deubiquitinating enzymes (DUBs) reverse the process of ubiquitination by removing ubiquitin from its substrate protein. (cellsignal.com)
  • The ubiquitination machinery can conjugate a single ubiquitin to one lysine residue of substrates (called mono-ubiquitination), multiple single ubiquitin molecules to multiple lysine residues (called multi-ubiquitination), or multiple ubiquitins in a chain (called poly-ubiquitination) to substrates. (frontiersin.org)
  • However, there is increasing evidence that the addition of a single ubiquitin molecule, mono-ubiquitination, is an important post-translational mechanism of modifying protein function ( Hicke, 2001 ). (jneurosci.org)
  • Ubiquitination requires a cascade of enzymes, with the target or substrate specificity finally defined by the E3 ubiquitin ligase component, a noncatalytic component of the active complex that is formed with an E2 ligase. (iucr.org)
  • Thus, Largazole and select analogs are a novel class of ubiquitin E1 inhibitors and valuable tools for studying ubiquitination in vitro. (sigmaaldrich.com)
  • In characterizing the system, we were the first to note that ubiquitination of the target protein may proceed in an E3-independent manner likely through auto-monoubiquitination involving a ubiquitin-binding domain (UBD). (cornell.edu)
  • E1 is also found to form complexes with ubiquitin conjugating enzymes and E3s [ 17 ]. (nottingham.ac.uk)
  • While there may be two or even three species of E1 in cells S. cerevisiae is currently known to contain at least 10 genes coding for ubiquitin-conjugating enzymes (E2). (nottingham.ac.uk)
  • There are three accessory enzymes that are involved in tagging a protein with ubiquitin, creatively named E 1 , E 2 and E 3 . (everything2.com)
  • Distinct requirements for charging of the ubiquitin conjugating enzymes Use1 and Cdc34 in vivo . (nature.com)
  • There are two classes of Dub enzymes, the Ubp family (ubiquitin-specific proteases) and the Uch family (ubiquitin carboxyterminal hydrolases). (genetics.org)
  • Ubp enzymes cleave ubiquitin from a range of substrates. (genetics.org)
  • Apg8 is a ubiquitin-like protein that is activated by an E1 protein, Apg7 (refs 7, 8), and is transferred subsequently to the E2 enzymes Apg3/Aut1 (ref. 9). (sigmaaldrich.com)
  • Interestingly, these modifying enzymes are themselves fine-tuned and precisely regulated at the level of protein turnover by ubiquitin-proteasomal processing. (mdpi.com)
  • Recently, ExoU has been established as a model protein for a group of ubiquitin-activated PLA 2 enzymes encoded by a variety of bacteria. (asm.org)
  • Here we make use of an Escherichia coli -based dual expression system to screen putative ubiquitin-activated PLA 2 enzymes from a variety of bacteria that are known to colonize humans and to cause human infections. (asm.org)
  • Conversely, ubiquitin was not found to regulate the activity of several other tested enzymes. (asm.org)
  • Similar to the founding member of the group, ExoU, these enzymes share the property of ubiquitin-mediated activation. (asm.org)
  • Ubiquitin-Activating Enzymes" is a descriptor in the National Library of Medicine's controlled vocabulary thesaurus, MeSH (Medical Subject Headings) . (harvard.edu)
  • A class of enzymes that catalyzes the ATP-dependent formation of a thioester bond between itself and UBIQUITIN. (harvard.edu)
  • This graph shows the total number of publications written about "Ubiquitin-Activating Enzymes" by people in Harvard Catalyst Profiles by year, and whether "Ubiquitin-Activating Enzymes" was a major or minor topic of these publication. (harvard.edu)
  • Below are the most recent publications written about "Ubiquitin-Activating Enzymes" by people in Profiles. (harvard.edu)
  • Ubiquitin is a protein of 76 amino acid residues, found in all eukaryotic cells and whose sequence is extremely well conserved from protozoan to vertebrates. (ebi.ac.uk)
  • Ubiquitin has seven lysine residues, any one of which can be used to link ubiquitin molecules together, resulting in different structures that alter the target protein in different ways. (ebi.ac.uk)
  • The result of this sequential cascade is to bind ubiquitin to lysine residues on the protein substrate via an isopeptide bond, cysteine residues through a thioester bond, serine and threonine residues through an ester bond, or the amino group of the protein's N-terminus via a peptide bond. (wikipedia.org)
  • Secondary ubiquitin molecules are always linked to one of the seven lysine residues or the N-terminal methionine of the previous ubiquitin molecule. (wikipedia.org)
  • These 'linking' residues are represented by a "K" or "M" (the one-letter amino acid notation of lysine and methionine, respectively) and a number, referring to its position in the ubiquitin molecule as in K48, K29 or M1. (wikipedia.org)
  • Polyubiquitylation occurs when the C-terminus of another ubiquitin is linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule, creating a chain. (wikipedia.org)
  • The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate lysine residues. (wikipedia.org)
  • Ubiquitin is a small protein of 76 amino acid residues with a mass of about 8.6 kilodaltons. (biocompare.com)
  • The surface interacting residues of UPL and the acceptor ubiquitin are shown here [7] . (proteopedia.org)
  • The first ubiquitin molecule is covalently bound through its C-terminal carboxylate group to a particular lysine, cysteine, serine, threonine or N-terminus of the target protein. (wikipedia.org)
  • Function: Ubiquitin exists either covalently attached to another protein, or free (unanchored). (abcam.com)
  • ubiquitin a peptide 76 amino acids in length that can be covalently attached to target lysines either as a monomer or as a lysine-linked polymer. (phosphosite.org)
  • Here, Prof. Adriano Marchese reports an important novel UBD that shows a preference for polyubiquitin chains versus mono-ubiquitin. (youtube.com)
  • Ubiquitin itself has exposed surface lysines which can be tagged, sometimes leading to chains of ubiquitin attached to a target protein. (everything2.com)
  • Electroporation of a mutated form of ubiquitin that cannot form K48-linked polyubiquitin chains into the embryonic retina did not affect axonal pathfinding but inhibited terminal branching of RGCs upon reaching the tectum. (sciencemag.org)
  • In mammalian cells, ubiquitin chains on the damaged mitochondria play critical roles to induce mitophagy. (eurekalert.org)
  • Poly-ubiquitin chains via Lysine-63 residue (K63) of ubiquitin and linear poly-ubiquitin chains appear to play non-proteolytic functions and are involved in DNA repair, NF-κB activation, and Ras localization and signaling, etc. (frontiersin.org)
  • Our data reveal unexpected complexity in the pathways that control the conjugation of ubiquitin, in which dual E1s orchestrate the charging of distinct cohorts of E2s. (nature.com)
  • Mechanism and role in protein-ubiquitin conjugation. (nature.com)
  • Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. (wikipedia.org)
  • We now report that Largazole and its ester and ketone analogs selectively inhibit ubiquitin conjugation to p27(Kip1) and TRF1 in vitro. (sigmaaldrich.com)
  • This cysteine accepts ubiquitin from E1 to form a thiol ester . (nottingham.ac.uk)
  • The activated ubiquitin is then transferred to an E2 cysteine. (wikipedia.org)
  • The E3 molecule is responsible for binding the target protein substrate and transferring the ubiquitin from the E2 cysteine to a lysine residue on the target protein. (wikipedia.org)
  • A thioester bond forms between the active cysteine residue of E1 and the C-terminus of ubiquitin in an ATP-dependent reaction. (frontiersin.org)
  • UPL contains an thioester-forming cysteine which catalyzes the transfer of ubiquitin from E2 to a substrate lysine. (proteopedia.org)
  • Through these steps, the ubiquitin molecule forms an isopeptide bond with the residue of lysine on the protein substrate respectively. (news-medical.net)
  • The terminal glycine in the C-terminal 4-residue tail of ubiquitin can form an isopeptide bond with a lysine residue in the target protein, or with a lysine in another ubiquitin molecule to form a ubiquitin chain that attaches itself to a target protein. (ebi.ac.uk)
  • The unfolding behavior of ubiquitin under the influence of a stretching force recently was investigated experimentally by single-molecule constant-force methods. (pnas.org)
  • Each additional ubiquitin moiety is attached via the internal lysine of the previously conjugated ubiquitin molecule. (frontiersin.org)
  • Here, we show that drugs that are known to reduce the level of free ubiquitin in the cell dramatically reduced the release of Rous sarcoma virus, an avian retrovirus. (pnas.org)
  • When expressed in yeast, the protein is post-translationally processed, generating free ubiquitin monomer and ribosomal protein S27a. (thermofisher.com)
  • Ubiquitin is a 76 amino acid (about 8.5 kDa ) protein found in most eukaryotes . (everything2.com)
  • The ubiquitin protein itself consists of 76 amino acids and has a molecular mass of about 8.6 kDa. (wikipedia.org)
  • This process most commonly binds the last amino acid of ubiquitin (glycine 76) to a lysine residue on the substrate. (wikipedia.org)
  • Ubiquitin is a small, 76-amino acid, regulatory protein that was discovered in 1975. (healthline.com)
  • Found in all eukaryotic cells with the same amino acid sequence, ubiquitin has been virtually unchanged by evolution. (healthline.com)
  • A ubiquitin ligase has dual functions in ABA-mediated drought stress and in amino acid export in Arabidopsis. (plantphysiol.org)
  • Finally, with the help of a ubiquitin-protein ligase, E3, a covalent bond is formed between the C-terminus of ubiquitin and the ε-amino group of a lysine residue on the protein substrate. (frontiersin.org)
  • 2006). The ubiquitin carboxyl-terminal hydrolase (UCH) catalytic core of the USPs is typically around 350 amino acids, but consists of six conserved boxes, interspersed by insertion sites for additional sequence that can confer diversity (Ye et al. (atlasgeneticsoncology.org)
  • The model is computationally efficient and allows for the collection of large amounts of unfolding events for ubiquitin, which is important because of the existence of multiple unfolding pathways. (pnas.org)
  • The chemical reactions and pathways resulting in the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of a ubiquitin group, or multiple ubiquitin groups, to the protein. (yeastgenome.org)
  • The successful candidate will work on a research project aiming to understand how the ubiquitin system controls inflammatory signalling and cellular metabolism and how dysregulation of these pathways may contribute to development of immune diseases and cancer. (dtu.dk)
  • We investigate how the ubiquitin system regulate signalling pathways at the interface of inflammation, cellular metabolism, and cell death, and how such signalling can contribute to disease development. (dtu.dk)
  • Pathways that involve ubiquitin underlie a multitude of processes, including cell differentiation, the cell cycle and responses to stress. (caltech.edu)
  • Boutell C, Canning M, Orr A, Everett RD. Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7. (springer.com)
  • Deubiquitination of NF-κB by ubiquitin-specific protease-7 promotes transcription. (springer.com)
  • Everett RD, Meredith M, Orr A, Cross A, Kathoria M, Parkinson J. A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. (springer.com)
  • The resulting ubiquitin-protein conjugates are degraded by the 26S proteasome, a large ATP-dependent protease. (caltech.edu)
  • These thiol proteases hydrolyze the amide bond between Gly76 of ubiquitin and a Lys residue of the substrate protein or preceding ubiquitin. (genetics.org)
  • Ubiquitin is a small protein that exists in all eukaryotic cells. (wikipedia.org)
  • Small protein tags such as ubiquitin have also been shown to control the activation of kinases. (genetics.org)
  • Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A. (wikipedia.org)
  • citation needed] Ubiquitin is encoded in mammals by 4 different genes. (wikipedia.org)
  • Whereas most previous efforts have focused on genetic mechanisms for the loss of metastasis suppressor genes, our results provide new evidence for post-translational downregulation of a metastasis suppressor by its ubiquitin ligase, resulting in abrogation of its metastasis-suppressing effects. (nature.com)
  • Ubiquitin is encoded by 4 different genes. (phosphosite.org)
  • At the protein level, it is not possible to determine which of the four genes a given ubiquitin chain was derived from. (phosphosite.org)
  • UBB is 1 of 2 genes encoding for ubiquitin as a polyprotein consisting of multiple copies of ubiquitin monomers. (jci.org)
  • A ) Expression of the 4 human genes that encode for ubiquitin - RPS27A (yellow), UBA52 (blue), UBB (red), and UBC (green) - along with GAPDH (gray), in 3 TCGA tumor types - lung (LUAD), ovarian (OV), and thyroid (THCA). (jci.org)
  • Gupta, the Ubiquitin-Proteasome system controls basic cellular processes such as cell division, cell signalling and gene regulation. (acronymfinder.com)
  • The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. (jci.org)
  • In this review, we highlight the molecular physiology and pharmacology of the proteasome and its upstream ubiquitin (Ub) system, with special attention to existing and promising modulators of this essential component of cellular physiology. (jci.org)
  • DUB activity maintains ubiquitin recycling and ensures the cellular pool of ubiquitin molecules remains steady. (cellsignal.com)
  • A 2017 study suggested that ubiquitin is also involved in other cellular processes, such as activation of nuclear factor-κB (NF-κB) inflammatory response and DNA damage repair. (healthline.com)
  • Ubiquitin plays an important role in regulating protein on the cellular level. (healthline.com)
  • The project will involve experimental laboratory work using molecular cell biology, cell culture systems, and biochemical approaches to understand how ubiquitin controls cell signalling and cell fate decisions at the interface of inflammation, cellular metabolism, and cell death. (dtu.dk)
  • The project is funded by the Novo Nordisk Foundation and will be focused on understanding how ubiquitin controls cell signalling and cell fate decisions at the interface of inflammation, cellular metabolism, and cell death. (dtu.dk)
  • Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental cellular events such as cell division and apoptosis, our data suggest a potential mechanism linking protein aggregation to cellular disregulation and cell death. (sciencemag.org)
  • Silencing of UBB reduces cellular UBB levels and results in an exquisite dependence on ubiquitin C (UBC), the second polyubiquitin gene. (jci.org)
  • Ubiquitin is important for nearly every aspect of cellular physiology. (mit.edu)
  • Viral involvement with ubiquitin occurs either adventitiously because of the unavoidable usurpation of cellular processes, or for some specific purpose selected for by the virus to enhance viral replication. (mit.edu)
  • Ubiquitin-like (ubl) modification is an example of post-translational modification (PTM) that influences a number of cellular processes. (cornell.edu)
  • The E2~Ub conjugate interacts with a ubiquitin ligase (E3) to transfer Ub to a lysine residue on a target protein. (rcsb.org)
  • Formation of a polyubiquitin chain occurs when a lysine residue of ubiquitin is linked to the carboxy-terminal glycine of another ubiquitin. (cellsignal.com)
  • Some E2s appear to require no other protein factor, at least in vitro, to transfer ubiquitin to a suitable target. (nottingham.ac.uk)
  • Here we identify a divergent E1 in vertebrates and sea urchin, Uba6, which specifically activates ubiquitin but not other UBLs in vitro and in vivo . (nature.com)
  • Human Uba6 and Ube1 have distinct preferences for E2 charging in vitro , and their specificity depends in part on their C-terminal ubiquitin-fold domains, which recruit E2s. (nature.com)
  • Uba6 activates ubiquitin in vitro . (nature.com)
  • SMER3 is a selective inhibitor of a yeast SCF family E3 ubiquitin ligase (SCFMet30) in vitro and in vivo. (adooq.com)
  • Several ubiquitin-like molecules have been discovered, such as Ufm1 ( IPR005375 ), SUMO1 ( IPR003653 ), NEDD8, Rad23 ( IPR004806 ), Elongin B and Parkin ( IPR003977 ), the latter being involved in Parkinson's disease [ PMID: 15564047 ]. (ebi.ac.uk)
  • Neuronal cell adhesion molecules "are critical in the development of the nervous system, contributing to axonal guidance, synaptic formation and plasticity, and neuronal-glial interactions," the researchers explained, while the ubiquitin-proteasome system "operates pre- and post-synaptic compartments, regulating synaptic attributes, including transmitter release, synaptic vesicle recycling in pre-synaptic terminals, and dynamic changes in dendritic spines and the post-synaptic density. (acronymfinder.com)
  • First, Yamano and colleagues found that mitophagy can be induced by a linear ubiquitin chain artificially targeted on the outer mitochondrial membrane, or by a chemical compound called SNIPER that induces ubiquitylation of a specific mitochondrial outer membrane protein. (eurekalert.org)
  • This necessity for the major part has been found to be taken care of by the ubiquitin-proteasome system (UPS). (springer.com)
  • examined the role of the ubiquitin-proteasome system in axonal branching of retinal ganglion cells (RGCs). (sciencemag.org)
  • Their paper, Chloroplast Biogenesis is Regulated by Direct Action of the Ubiquitin-Proteasome System , is due to be published in the journal Science on November 2. (acronymfinder.com)
  • Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. (acronymfinder.com)
  • The 26S proteasome is a highly abundant ~2 MDa complex that serves as the proteolytic arm of the ubiquitin-proteasome system. (cellsignal.com)
  • Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. (sciencemag.org)
  • GFP u is a substrate of the ubiquitin-proteasome system. (sciencemag.org)
  • Our findings identify an essential function for the ubiquitin-proteasome-system in spermiogenesis and define a novel, non-redundant physiological function for the dislocation step of ER quality control. (mit.edu)
  • The ubiquitin-proteasome system (UPS) has been increasingly recognized as a major system involved in several biological processes such as cell proliferation, adaptation to stress and cell death. (biovision.com)
  • Thus, Doa4p may promote proteolysis by increasing ubiquitin pools and removing proteolytic remnants that would otherwise inhibit proteasome activity by a negative feedback mechanism. (genetics.org)
  • C ) Lysates of untransfected HEK or GFP u -1 cell were treated overnight with the proteasome inhibitor ALLN, or mock-treated, as indicated, immunoprecipitated with anti-GFP, and immunoblotted with a ubiquitin monoclonal antibody. (sciencemag.org)
  • Small ubiquitin-related modifier 1, 2, and 3 (SUMO-1, -2, and -3) and NEDD8 are members of the ubiquitin-like protein family. (cellsignal.com)
  • SUMO versus Ubiquitin: A Fight for Huntington's Disease? (alzforum.org)
  • Ubiquitin may be everywhere, but when it comes to polyglutamine diseases like Huntington's (HD), SUMO-1 (small ubiquitin-like modifier 1) may have just as much clout, report Lawrence Marsh and colleagues from University of California, Irvine, in today's Science. (alzforum.org)
  • Figure 1: The ubiquitin-protein ligase activity of gp78 is required for metastasis of HT1080 sarcoma cells. (nature.com)
  • Both ZNRF1 and ZNRF2 have E3 ubiquitin ligase activity and are highly expressed in the nervous system, particularly during development. (jneurosci.org)
  • also known as Gm288 in mouse and CCNB1IP1 in human), a putative B-type cyclin E3 ubiquitin ligase. (middlebury.edu)
  • Boston Biochem is committed to providing flexible, high quality, and confidential protein biochemistry contract services for Ubiquitin-focused research. (rndsystems.com)
  • Dislocation substrates are ubiquitylated in the cytosol by E2 ubiquitin-conjugating/E3 ligase complexes. (mit.edu)
  • Ubiquitin, also known as RPS27A, is the full name of UBB. (biocompare.com)
  • Ubiquitin Ligase (E3) Inhibitors " has 34 results in Products. (rndsystems.com)
  • human and yeast ubiquitin share 96% sequence identity. (wikipedia.org)
  • The protein modifications can be either a single ubiquitin protein (monoubiquitylation) or a chain of ubiquitin (polyubiquitylation). (wikipedia.org)
  • The following antibody was used in this experiment: Ubiquitin Polyclonal Antibody from Thermo Fisher Scientific, catalog # PA5-72439, RRID AB_2718293. (thermofisher.com)
  • This gene encodes a fusion protein consisting of ubiquitin at the N terminus and ribosomal protein S27a at the C terminus. (thermofisher.com)
  • similarly, ribosomal protein S30 is synthesized as a fusion protein with the ubiquitin-like protein fubi. (thermofisher.com)
  • Ubiquitin-like modifiers may produce similar results to ubiquitin although in some cases they can be distinctly different. (news-medical.net)
  • Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975 as an 8.6 kDa protein expressed in all eukaryotic cells. (wikipedia.org)
  • Polypeptide sequences attached to the ubiquitin protein. (creation.com)
  • Antibodies to Ubiquitin can be used to study cell differentiation and development. (biocompare.com)
  • Your search returned 17192 Ubiquitin Antibodies across 63 suppliers. (biocompare.com)
  • Listed below are anti-ubiquitin antibodies from various suppliers. (biocompare.com)
  • Your search returned 1347 Ubiquitin Antibodies across 1 supplier. (biocompare.com)
  • We show that Largazole and its derivatives specifically inhibit the adenylation step of the E1 reaction while having no effect on thioester bond formation between ubiquitin and E1. (sigmaaldrich.com)
  • The ubiquitin system has been implicated in the immune response, development, and programmed cell death. (nih.gov)
  • In this review we discuss recent information on functions and mechanisms of the ubiquitin system. (nih.gov)
  • see the Perspective by Mukherjee and Orth) describe a ubiquitin-like protein system they call Pup in prokaryotes. (sciencemag.org)
  • A 2018 study suggested that dysfunction of the ubiquitin system can lead to neurodegenerative disorders and other human diseases. (healthline.com)
  • This study also indicates that the ubiquitin system is involved in the development of inflammatory and autoimmune diseases, such as arthritis and psoriasis . (healthline.com)
  • However, because of its diverse and complicated nature, the mechanisms behind the physiological and pathophysiological actions of the ubiquitin system aren't yet fully understood. (healthline.com)
  • A ubiquitin-like system mediates protein lipidation. (sigmaaldrich.com)
  • The ubiquitin system is critical for controlling innate immune signalling and transcription factor activation. (dtu.dk)
  • Eine wichtige Rolle spielt in diesem Zusammenhang die effiziente Generierung von Tumorepitopen durch das Ubiquitin-Proteasom-System (UPS). (hu-berlin.de)
  • Ubiquitin is an important regulatory protein found in almost all eukaryote tissue. (youtube.com)
  • Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. (wikipedia.org)
  • The block to budding was found to be at the plasma membrane, and electron microscopy revealed that the reduced level of ubiquitin results in a failure of mature virus particles to separate from each other and from the plasma membrane during budding. (pnas.org)
  • Thus, we describe a recurrent cancer-specific lesion at the level of ubiquitin production. (jci.org)
  • In many cases, the ubiquitin tag consists of a chain of ubiquitin domains (polyubiquitin), which is formed by linkages between an exposed lysine side chain (Lys-11, -29, -48, or -63) of the last ubiquitin of a growing chain and the C terminus of a new ubiquitin. (pnas.org)