Author Summary Knotted proteins provide an ideal ground for examining how amino acid interactions (which are local) can favor their folding into a native state of non-trivial topology (which is a global property). Some of the mechanisms that can aid knot formation are investigated here by comparing coarse-grained folding simulations of two enzymes that are structurally similar, and yet have natively knotted and unknotted states, respectively. In folding simulations that exclusively promote the formation of native contacts, neither protein forms knots. Strikingly, when sequence-dependent non-native interactions between amino acids are introduced, one observes knotting events but only for the natively-knotted protein. The results support the importance of non-native interactions in favoring or disfavoring knotting events in the early stages of folding.
For several decades, the presence of knots in naturally-occurring proteins was largely ruled out a priori for its supposed incompatibility with the efficiency and robustness of folding processes. For this very same reason, the later discovery of several unrelated families of knotted proteins motivated researchers to look into the physico-chemical mechanisms governing the concerted sequence of folding steps leading to the consistent formation of the same knot type in the same protein location. Besides experiments, computational studies are providing considerable insight into these mechanisms. Here, we revisit a number of such recent investigations within a common conceptual and methodological framework. By considering studies employing protein models with different structural resolution (coarse-grained or atomistic) and various force fields (from pure native-centric to realistic atomistic ones), we focus on the role of native and non-native interactions. For various unrelated instances of knotted
In any normally functioning cell, two systems maintain protein quality. First, chaperone proteins, like fingers that fold paper into origami shapes, guide amino acid chains in folding into their final, proper protein forms. Second, the recycling systems dispose of misfolded proteins and ultimately breaks them up into individual amino acids. This system involves the proteasome, a protein complex found throughout the cytoplasm and nucleus of cells. But it is unclear how misshapen proteins are recognized and shuttled to the proteasome to be degraded. This study moves the field forward because we showed that the system is common for many types of misfolded proteins, notes Yang.. In addition to identifying the step-by-step molecular players of the system that eliminates misfolded proteins, they also defined the systems method of action. The mechanism of action is a relay system with two proteins.. The first protein, PML/TRIM19, recognizes features of misfolded proteins such as exposed water-phobic ...
Protein folding is a complex process involving van der Waals and hydrophobic interactions, electrostatics, and hydrogen bonding networks. One approach to understanding protein folding is to design from scratch a particular protein fold, thoroughly characterize its solution properties, and determine its three-dimensional structure. The field of de novo protein design (1, 2) has experienced some recent exciting successes in the redesign of natural proteins to incorporate novel, functional metal-binding sites (3, 4). Also, the redesign of proteins patterned after the sequence or three-dimensional structural motifs such as the zinc finger (5-8), coiled coils (9), or other small protein domains (10, 11) has progressed quite significantly. Unnatural right-handed coiled coils have been successfully designed (12), and small, marginally stable models for protein secondary (13, 14) and supersecondary structures, including helix-loop-helix (15, 16) and three-stranded β-hairpin motifs (17-20), have been ...
Proteins can sometimes be knotted, and for many reasons the study of knotted proteins is rapidly becoming very important. For example, it has been proposed that a knot increases the stability of a protein. Knots may also alter enzymatic activities and enhance binding. Moreover, knotted proteins may even have some substantial biomedical significance in relation to illnesses such as Parkinsons disease. But to a large extent the biological role of knots remains a conundrum. In particular, there is no explanation why knotted proteins are so scarce. Here we argue that knots are relatively rare because they tend to cause swelling in proteins that are too short, and presently short proteins are over-represented in the Protein Data Bank (PDB). Using Monte Carlo simulations we predict that the figure-8 knot leads to the most compact protein configuration when the number of amino acids is in the range of 200-600. For the existence of the simplest knot, the trefoil, we estimate a theoretical upper bound ...
A Two-Layer Learning Architecture for Multi-Class Protein Folds Classification: 10.4018/978-1-4666-3604-0.ch041: Classification of protein folds plays a very important role in the protein structure discovery process, especially when traditional sequence alignment methods
2004 (English)In: Proc Natl Acad Sci U S A, ISSN 0027-8424, Vol. 101, no 17, 6450-5 p.Article in journal (Refereed) Published ...
Despite the vast number of amino-acid sequences, protein folds (or superfamilies) are quantitatively limited [1-4]. Consequently, protein fold classification is an important subject for elucidating the construction of protein tertiary structures. A key word to characterize protein folds is hierarchy. Well-known databases - SCOP [5] and CATH [6] - have classified the tertiary structures of protein domains hierarchically. Similarly, a tree diagram was produced to classify the folds [7].. Mapping the tertiary structures of full-length protein domains to a conformational space, a structure distribution is generated: a so-called protein fold universe [8-11]. A key word to characterize the fold universe is space partitioning. A two-dimensional (2D) representation of the fold universe was proposed in earlier reports [12, 13], where the universe was partitioned into three fold (α, β, and α/β) regions. A three-dimensional (3D) fold universe was partitioned into four fold regions: all-α, all-β, ...
1CIQ: Towards the complete structural characterization of a protein folding pathway: the structures of the denatured, transition and native states for the association/folding of two complementary fragments of cleaved chymotrypsin inhibitor 2. Direct evidence for a nucleation-condensation mechanism
Proteins do not fold by randomly searching a large number of nearly degenerate configurations; instead, an ensemble of unfolded molecules must traverse a complicated energy landscape to reach a thermodynamically stable structure. The fastest nuclear motions in proteins, rotations about single bonds, occur on the picosecond time scale and accompany both secondary- and tertiary-structure-forming processes. Short segments of secondary structure (e.g., α-helices) can be formed in nanoseconds, whereas the large-scale, collective motions associated with the development of tertiary structure fall in the microsecond to millisecond range. Misfolded structures or traps are frequently encountered in folding processes; escape from these traps (e.g., proline isomerization) can take seconds or even minutes. Understanding the key events in folding and identifying any partially folded intermediates are major goals of theoretical and experimental work. ...
1CIQ: Towards the complete structural characterization of a protein folding pathway: the structures of the denatured, transition and native states for the association/folding of two complementary fragments of cleaved chymotrypsin inhibitor 2. Direct evidence for a nucleation-condensation mechanism
The three-state model of Dunham et al. 1993 is among the simplest mechanisms containing more than one event in the activation-inactivation process. However, m
Protein folds show more flexibility than previously thought, but the flexibility appears designed. If its hard to get one fold to work, how about two in the…
This is what scientists were waiting for when the HIV virus was first tampered with. There are proteins in HIV that can be very very useful if mutated to created a proper protein for it. I imagine the purpose of this. You can imagine HIVs Multi-viral properties. HIV is known to rapidly evolve into different shaped cells which is why its so hard to target. But, i imagine that if this tamed it could possibly be used to convert any cell into a different cell. They were waiting for this to happen so they could nab that guy and extract that genome. The thing about HIV is its a super virus and it it gets tamed you can assure it will evolve up another stage which would produce some pretty deadly viruses that will be hazardous to anyone who does not have the immunity. But beyond this, it can be used to rapidly evolve the human race if they extract that genome. Its somewhat more important than simply just a cure we are talking about a virus that can PWN other disease that try to enter your body if the ...
Proteins, the ubiquitous workhorses of biochemistry, are huge molecules whose function depends on how they fold into intricate structures. To understand how these molecules work, researchers use c ...
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No mention of MS, and they say that, The split-second folding of gangly protein chains into tight three-dimensional shapes has broad implications for the growing number of disorders believed to result from misfolded proteins or parts of proteins, most notably ...
We had a great discussion, but I wanted to start it over. This is esp so we can have others join us. So Introduce yourself and.. -discuss what brought
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ヒト肝炎ウィルスの分子形態学的研究 : 特にヒトB型肝炎ウィルスのnative structureについて(受賞講演(1),第48回日本組織細胞化学会総会(第8回日中合同組織細胞化学セミナー) 第39回日本臨床分子形態学会総会 合同学術集会) (2007 ...
All proteins that transit the secretory pathway in eukaryotic cells first enter the endoplasmic reticulum (ER), where they fold and assemble into multisubunit complexes prior to transit to the Golgi compartment [1]. Quality control is a surveillance mechanism that permits only properly folded proteins to exit the ER en route to other intracellular organelles and the cell surface. Misfolded proteins are either retained within the ER lumen in a complex with molecular chaperones or are directed toward degradation through the 26S proteasome in a process called ER-associated degradation (ERAD) or through autophagy. PROTEIN FOLDING AND QUALITY CONTROL IN THE ER Protein folding and maturation in vivo is a highly assisted process. The ER lumen contains molecular chaperones, folding enzymes, and quality control UPR SIGNALING 23 factors that assist in folding and trafficking of newly synthesized polypeptides. Nascent polypeptide chains enter the ER lumen through a proteinaceous channel, the Sec 61 ...
As a consequence of the rugged landscape of RNA molecules their folding is described by the kinetic partitioning mechanism according to which only a small fraction ($\phi_F$) reaches the folded state while the remaining fraction of molecules is kinetically trapped in misfolded intermediates. The transition from the misfolded states to the native state can far exceed biologically relevant time. Thus, RNA folding in vivo is often aided by protein cofactors, called RNA chaperones, that can rescue RNAs from a multitude of misfolded structures. We consider two models, based on chemical kinetics and chemical master equation, for describing assisted folding. In the passive model, applicable for class I substrates, transient interactions of misfolded structures with RNA chaperones alone are sufficient to destabilize the misfolded structures, thus entropically lowering the barrier to folding. For this mechanism to be efficient the intermediate ribonucleoprotein (RNP) complex between collapsed RNA and ...
Free radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases, because in the majority of cases it is a non-reversible phenomenon that requires clearance systems for removal. Major consequences of protein oxidation are loss of protein function and the formation of large protein aggregates, which are often toxic to cells if allowed to accumulate. Deposition of aggregated, misfolded, and oxidized proteins may also result from the impairment of protein quality control (PQC) system, including protein unfolded response, proteasome, and autophagy. Perturbations of such components of the proteostasis network that provides a critical protective role against stress conditions are emerging as relevant factor in triggering neuronal death. In this outlook paper, we discuss the role of protein oxidation as a major contributing factor for the impairment of the PQC regulating protein folding, surveillance, and degradation. Recent studies from our group and from
Refolding of proteins is traditionally carried out either by diluting the denaturant-unfolded protein into buffer (GdmCl-jump) or by mixing the acid-denatured protein with strong buffer (pH-jump). The first method does not allow direct measurement of folding rates in water since the GdmCl cannot be infinitely diluted, and the second method suffers from the limitation that many proteins cannot be pH-denatured. Further, some proteins do not refold reversibly from low pH where they get trapped as aggregation prone intermediates. Here, we present an alternative approach for direct measurement of refolding rates in water, which does not rely on extrapolation. The protein is denatured in SDS, and is then mixed with -cyclodextrin, which rapidly strips SDS molecules from the protein, leaving the naked unfolded protein to refold.. ...
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Glaucoma, a leading cause of blindness, is managed medically by treating the causal risk factor of increased intraocular pressure (IOP), which is typically obse...
Bacterial inclusion bodies are microscopic, ovoid-shaped aggregates of insoluble protein. Under protease exposure a digestion process is produced that reveals a variable fragmentation rate, not compatible with a surface restricted erosion of body particles, or an uniform sensibility to the fragmentation agent. The modelling and fitting of experimental data is performed in two steps. (a) Due to poor estimation of protein amounts only first derivatives can be numerically evaluated, and a non-linear first-order fragmentation model is adopted. Although it is a very good approximation for intermediate points, the asymtotic behaviour of the solution is inconsistent with the fragmentation process. (b) The solution of previous kinetic modelling is used to compute higher-order derivatives in intermediate points and to adopt a higher-order lineal model for the overall interval with protein fragmentation. The resulting model consists in a superposition of Poisson processes associated with several ...
Author Summary Most proteins are functional only in their native states. The stability of the native state of proteins is, therefore, of paramount importance both in vivo and for many biotechnological applications in vitro. Protein stability is determined by the difference between the free energies of the native and non-native states. It follows that protein stabilization can be achieved via two different strategies: (i) positive design by introducing favorable interactions between residues in contact in the native state; and (ii) negative design by introducing unfavorable interactions between residues in contact in the non-native states. Here, we ask when is one strategy favored over the other. We show that positive design is favored when interactions that stabilize the native state are rarely found in the non-native states whereas negative design is favored when the interactions that stabilize the native state are also common in the non-native states. We also show that correlated mutations, i
It is crucial for the Tat system to sense when complex proteins are fully ready for export, and several studies have investigated these issues with various redox proteins (Oresnik et al, 2001; Sargent, 2007; Schubert et al, 2007). Our studies on NrfC and NapG have shown that the Tat pathway recognizes when these proteins are misfolded or unable to assemble a full complement of FeS centres, and export is blocked (Matos et al, 2008). The study has also identified an additional and unexpected facet of NrfC/NapG export, in that the Tat system itself initiates the degradation of misfolded forms.. Here, we have identified TatD as a central element of this quality control system. This is surprising because TatD is not required for Tat export activity and the presence of the tatD gene in the tat operon has been regarded as fortuitous (Wexler et al, 2000). We found that TatD is not required for the export of NrfC, but is essential for the rapid turnover of mutated NrfC and NapG. These proteins are ...
A proteins function in the cell depends on its structure, which in turn depends on the intracellular environment. Stress like heat shock or nutrient starvation can alter intracellular conditions, leading to protein misfolding - i.e. the inability of a protein to reach or maintain its native conformation. Since many proteins interact with each other, protein misfolding and cellular stress response must be examined both on the scale of individual protein conformational changes and on a more global level, where interaction patterns can reveal larger-scale protein responses to cellular stress. On the individual scale, one example of a protein particularly susceptible to misfolding is the human von Hippel-Lindau (VHL) tumor suppressor. When expressed in the absence of its cofactors, VHL cannot fold correctly and is quickly degraded by the cells quality control machinery. Here, I present a biophysical characterization of a VHL mutation that confers increased resistance to misfolding. Mathematical ...
Molecular chaperones are central components of the cellular machinery that maintains protein homeostasis, and therefore have fundamental impact on cell physiology, aging and disease. Our goal is to understand the mechanisms of chaperone networks in protein biogenesis and quality control, and how these networks relate to cancer and neurodegeneration. We have three main research themes: (1) Biogenesis of proteins: A multi-layered machinery engages translating ribosomes to promote folding of newly synthesized proteins. We want to understand how this machinery guides nascent polypeptides to the native state, and how assembly of oligomeric protein complexes are achieved. (2) Cellular protein quality control: Perturbation of proteostasis activates quality control systems which refold and degrade misfolded proteins or sequester them into aggregates. We are investigating the organised aggregation of proteins in cells, and the mechanisms by which chaperones rescue aggregated proteins. (3) Propagation of ...
Protein-protein interactions are of fundamental importance to molecular biology because they determine a wide array of protein structures and functions. In addition to heterogeneous protein-protein complexes, many proteins are oligomeric due to the association of identical subunits. In fact, the majority, 70-80 %, of all enzymes are oligomeric [1]. The function of quaternary structure, i.e. the arrangement of multiple subunits into an oligomer, may be to allow for cooperative effects, formation of novel active sites, provide additional stability, increase solubility or decrease osmotic pressure [2]. The folding pathways of only a few oligomeric proteins (mostly dimers and tetramers) have been reported, revealing a variety of mechanisms [3-7]. Some proteins display monomeric or dimeric intermediates (e.g. E. coli Trp repressor and the ATPase SecA [8, 9]) whereas other fold in apparent two-state reactions in which folding and oligomerization are coupled (e.g. P22 Arc repressor [10, 11]). It ...
Proteins are the workhorses of the cell, and their correctly folded three-dimensional structures are critical to cellular functions. Misfolded structures often fail to properly perform these vital jobs, leading to cellular stress and devastating neurodegenerative disorders such as Huntingtons disease. Researchers will describe their multipronged efforts to gain a better understanding of the relationship between protein misfolding, aggregation and cell toxicity at the 58th Annual Biophysical Society Meeting.
A number of human diseases are known to result, directly or indirectly, from aberrant protein folding reactions. In addition to loosing their normal function, misfolded polypeptides may form toxic species, may exert dominant negative effects, or may not reach their proper cellular location. Recently, a direct involvement of molecular chaperones in human disorders has become increasingly evident. A major area of research in my laboratory is to study proteins with similarities to molecular chaperones that, when mutated, lead to neurodegenerative disorders. Expression of eukaryotic proteins in bacterial hosts often results in misfolding and aggregation, which has placed great limitations on their recombinant production. Another area of my research focuses on the mechanisms underlying the inability of the bacterial cytosol to support efficient folding of eukaryotic multi-domain proteins. We have found that bacteria and eukaryotes utilize markedly different pathways for de novo protein folding, and ...
At the moment, Im reading The role of molecular chaperones in human misfolding diseases [PDF] by Sarah A. Broadley and F. Ulrich Hartl of the Max Planck Institute of Biochemistry. Its a good overview of the subject, with 107 references, mostly from 2002 on ...
Yadav, Subhash Chandra, Prasanna Kumari, N. K. and Jagannadham, Medicherla V. 2010, Deglycosylated milin unfolds via inactive monomeric intermediates, European biophysics journal, vol. 39, no. 12, pp. 1581-1588, doi: 10.1007/s00249-010-0615-x. ...
Some proteins contain locally knotted structures. Many algorithms have been developed in order to detect local knotting in protein conformations. In some cases these algorithms are used to rule out computationally generated structures containing local knots as knotted proteins are rare. However, there are several types of proteins which contain local knots. I will give an
Drips (Susan S. Roberts. 2007) A while ago, I posted a brief extract from a 2008 paper from Drummond & Wilke ((Mistranslation-Induced Protein Misfolding as a
NIH Funding Opportunities and Notices in the NIH Guide for Grants and Contracts: Targeting Diseases Caused by Protein Misfolding or Misprocessing (R01) PAR-06-479. NIDDK
To ensure proper folding, cells have evolved a sophisticated and essential machinery of proteins called molecular chaperones that assist the folding of newly made polypeptides. The importance of proper protein folding is underscored by the fact that a number of diseases, including Alzheimers and those involving infectious proteins (prions), result from protein-misfolding events. My research focuses on identifying and understanding the machinery necessary for efficient folding, as well as studying the mechanism and consequences of protein misfolding. We are also developing experimental and analytical approaches for exploring the organizational principles of complex biological systems.
The foundation of TPS is our prestigious journal, Protein Science. With a storied history that includes past Editors in Chief: Hans Neurath, Mark Hermodson, and current editor, Brian Matthews, and a reputation for featuring leading-edge protein research through innovative means, the Journal has grown to become the premier platform for scientists all around the world with a trans-disciplinary focus on proteins. Subject matter encompasses protein structure, function, design, and applications, exploring proteins critical roles in molecular and cell biology, genetics, proteomics, evolution, and more.. ...
MyJournals.org - Science - Molecules, Vol. 25, Pages 251: Structural Disorder in High-Spin {CoII9WV6} (Core)-[Pyridine N-Oxides] (Shell) Architectures (Molecules)
The onslaught of COVID-19 has raised the visibility of the [email protected] project, highlighting a unique opportunity to fight the virus. The project seeks to understand how proteins, which are large, complex molecules that play an important role in how our bodies function, fold to perform their biological functions. This helps researchers understand diseases that result from protein misfolding and identify novel ways to develop new drug therapies.. How proteins fold or misfold can help us understand what causes diseases like cancer, Alzheimers disease and diabetes. It might also lend insight into viruses such as SARS-CoV-2, the cause of the recent COVID-19 pandemic. Imagine if I told 100 people to fold a pipe cleaner. They are going to fold it in 100 different ways because theres an infinite number of combinations of how to take something that is straight and fold it, said Blake Joyce, assistant director of research computing at the University of Arizona. Thats what viruses and living ...
Protein Science The section deals broadly with proteins as the cells and organs work horses, trying to understand the biological processes and systems from a molecular understanding of the proteins properties. We analyse the proteins physical and chemical structures and their functions under physiologically relevant conditions. Specific areas include: Research areas and projects:. ...
Protein Science The section deals broadly with proteins as the cells and organs work horses, trying to understand the biological processes and systems from a molecular understanding of the proteins properties. We analyse the proteins physical and chemical structures and their functions under physiologically relevant conditions. Specific areas include: Research areas and projects:. ...
Protein Science & Mass Spec | The Tecan Journal is published several times a year, and contains articles featuring users of Tecan instruments, as well as information about latest products and global Tecan activities.
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Protein structures adopt1 many different folds - or shapes. These can be protein classification|classified under various schemes, but it is sometimes di...
The seemingly limitless diversity of proteins in nature arose from only a few thousand domain prototypes, but the origin of these themselves has remained unclear. We are pursuing the hypothesis that they arose by fusion and accretion from an ancestral set of peptides active as co-factors in RNA-dependent replication and catalysis. Should this be true, contemporary domains may still contain vestiges of such peptides, which could be reconstructed by a comparative approach in the same way in which ancient vocabularies have been reconstructed by the comparative study of modern languages. To test this, we compared domains representative of known folds and identified 40 fragments whose similarity is indicative of common descent, yet which occur in domains currently not thought to be homologous. These fragments are widespread in the most ancient folds and enriched for iron-sulfur- and nucleic acid-binding. We propose that they represent the observable remnants of a primordial RNA-peptide world ...
The seemingly limitless diversity of proteins in nature arose from only a few thousand domain prototypes, but the origin of these themselves has remained unclear. We are pursuing the hypothesis that they arose by fusion and accretion from an ancestral set of peptides active as co-factors in RNA-dependent replication and catalysis. Should this be true, contemporary domains may still contain vestiges of such peptides, which could be reconstructed by a comparative approach in the same way in which ancient vocabularies have been reconstructed by the comparative study of modern languages. To test this, we compared domains representative of known folds and identified 40 fragments whose similarity is indicative of common descent, yet which occur in domains currently not thought to be homologous. These fragments are widespread in the most ancient folds and enriched for iron-sulfur- and nucleic acid-binding. We propose that they represent the observable remnants of a primordial RNA-peptide world ...
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A team of researchers of the International School for Advanced Studies (SISSA) of Trieste and of University of Cambridge have devised a method to reduce the time used to simulate how proteins take on their signature three-dimensional ...
The free energy landscape and the folding mechanism of the C-terminal beta-hairpin of protein G is studied by extensive replica… Expand ...
In many modern animated movies, the trick to achieving realistic movements for individual characters and objects lies in motion-capture technology.
Cellular survival relies crucially on the ability to receive and communicate signals from and to the outside world. A major part of this regulation and communication is performed by proteins within the membrane of a cell.
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In its native state, which of the following elements has bonds between many cations and a sea of valence electrons? Cl He Zn...
A team of researchers used simulations and X-rays to conclude that disordered proteins remain unfolded and expanded as they float loose in the cytoplasm of a cell. The answer affects how we envision the movement of a protein through its life-essential for understanding how proteins fold, what goes wrong during disorders and disease and how to model their behavior. ...
In the minimalist mid-1990s--so fraught with peril and an odd, defiant kind of hope--emerges the necessity of deliberate choice, of making California happen once again, as a matter of vision and