• Two arginines in this domain are responsible for hydrogen bonding phosphotyrosine residues on an Ac-LYASSNPApY-NH2 peptide in the juxtamembrane region of the insulin receptor. (wikipedia.org)
  • Different families of SH2 domains may have different binding specificity, which is usually determined by a few residues C-terminal with respect to the pY (positions +1 to +4). (eu.org)
  • The residue at pY+2 does not make direct side chain interactions with the SH2 domain, but aromatic residues are not allowed. (eu.org)
  • Positively charged residues are disfavoured at pY-1 and pY-2 due to the positively charged SH2 domain surface, but are tolerated when pY+1 and pY+3 are strong residues. (eu.org)
  • This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. (umbc.edu)
  • In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. (umbc.edu)
  • AFAP1L1 intersects several invadopodia pathway components through its multiple domains and motifs, including the following (i) pleckstrin homology domains that bind phospholipids generated at the plasma membrane by phosphoinositide 3-kinase, (ii) a direct filamentous-actin binding domain and (iii) phospho-tyrosine motifs (pY136 and pY566) that specifically bind Vav2 and Nck2 SH2 domains, respectively. (nature.com)
  • The Tir protein of EPEC binds NCK1/NCK2 SH2 domains through a high affinity pYDEV motif ( Frese,2006 ). (eu.org)
  • The intracellular region contains the kinase domain sandwiched between the juxtamembrane domain used for docking insulin-receptor substrates (IRS), and the carboxy-terminal tail that contains two phosphotyrosine-binding sites. (rndsystems.com)
  • Non-phosphorylated peptides do not bind to the SH2 domains. (eu.org)
  • Adam Kashishian (Fred Hutchinson Cancer Research Center, Seattle): "The question of the specificity of Src homology 2 (SH2) domain/phosphotyrosine interactions has been an important one since the ability of the SH2 domains to bind phosphotyrosine- containing peptides was first shown. (the-scientist.com)
  • The protease not only releases small peptides, such as the amyloid-β peptide, which drives Alzheimer's disease pathogenesis, but also intracellular domains, which can have critical functions in nuclear signaling. (cipsm.de)
  • Insulin receptor substrate-1 proteins contain both a pleckstrin homology domain and a phosphotyrosine binding (PTB) domain. (wikipedia.org)
  • The VEE is a heterogeneous compartment containing the Adaptor Protein Phosphotyrosine Interacting with Pleckstrin homology Domain and Leucine Zipper 1 (APPL1) with distinct functions in regulating endosomal Gαs/cAMP signaling and rapid recycling. (frontiersin.org)
  • These phosphotyrosine motifs are essential for AFAP1L1-mediated cytoskeleton regulation. (nature.com)
  • They are able to bind specific motifs containing a phosphorylated tyrosine residue, propagating the signal downstream by promoting protein-protein interactions and/or modifying enzymatic activities. (eu.org)
  • Several different binding motifs are known, for example: pYEEI (Src-family SH2 domains), pY [IV]. (eu.org)
  • The C-terminal half of the SH2 domain exhibits greater structural variability and provides a platform for accommodating different kinds of SH2-binding motifs. (eu.org)
  • Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. (embl-heidelberg.de)
  • They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. (embl-heidelberg.de)
  • Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. (embl-heidelberg.de)
  • The CCM2 phosphotyrosine binding (PTB) domain is necessary for a canonical interaction with NPxY motifs within CCM1. (unc.edu)
  • The human NCK1 (Nckα) and NCK2 (Nckβ/GRB4) SH2 domains show a degree of partner specificity but share the same mode of ligand binding ( Frese,2006 ) and belong to the class IA family which contains an aromatic residue (Phe) at the specificity-determining βD5 position ( Kaneko,2010 ). (eu.org)
  • The binding affinity of an SH2 domain to a pTyr containing ligand is moderate, with the typical affinity range between 0.1 µМ to 10 µМ for equilibrium dissociation constant values (Kd) ( Kaneko,2012 ). (eu.org)
  • In the canonical mode of SH2 binding, regions on either side of the central β sheet are involved in ligand binding. (eu.org)
  • The spacing of the cysteines in such a domain is C-x(2)-C-x(9 to 39)-C-x(1 to 3)-H-x(2 to 3)-C-x(2)-C-x(4 to 48)-C-x(2)-C. Metal ligand pairs one and three co-ordinate to bind one zinc ion, whilst pairs two and four bind the second. (embl-heidelberg.de)
  • The α-adrenergic receptor is described by seven α-helical transmembrane (TM) domains which form a 'crevice' for ligand binding. (pharmacology2000.com)
  • The alpha subunit is localized extracellularly and mediates ligand binding while the transmembrane beta subunit contains the cytoplasmic kinase domain and mediates intracellular signaling. (rndsystems.com)
  • Ligand binding induces a conformational change of the receptor, resulting in ATP binding, autophosphorylation, and subsequent downstream signaling. (rndsystems.com)
  • Not shown here is the activation under certain conditions of Jaks that are bound to some G-protein-coupled receptors (GPCRs) and the phosphorylation of STATs directly by certain ligand-activated growth factor receptors (RTKs) as well as non-receptor tyrosine kinases. (shu.edu)
  • Mutations in the tyrosine kinase, whether in BCR-ABL in CML or a FLT3 mutation in AML, bypass control that comes from ligand binding. (shu.edu)
  • The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif. (wikipedia.org)
  • Val and Pro confer high-affinity binding at pY+3 - Ala and Ile are tolerated but confer weaker binding. (eu.org)
  • Comparison of the X-ray structures shows that the presence of the H-bond acceptors and not their relative position within the pharmacophore are essential for fragment binding and/or high affinity binding of full length inhibitors. (rcsb.org)
  • Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity binding to membrane protein sorting signals. (sdbonline.org)
  • Both the A and B isoforms bind insulin with high-affinity, but the A isoform has considerably higher affinity for IGF‑I and IGF-II. (rndsystems.com)
  • The phosphotyrosine-binding domain of insulin receptor substrate-1 is not related to the phosphotyrosine-binding domain of tensin. (wikipedia.org)
  • The PTB domains facilitate interaction with the activated tyrosine-phosphorylated insulin receptor. (wikipedia.org)
  • When cytokines bind to their cognate receptor, JAKs phosphorylate the cytokine receptor and subsequently the STATs, which then dissociate from the JAK-receptor complex. (medscape.com)
  • Receptor dimerization and autophosphorylation attracts proteins containing Src homology 2 (SH2) or phosphotyrosine binding (PTB) domains including adaptor proteins like FRS2 and GRB2. (springer.com)
  • A. Kashishian, A. Kazlauskas, J.A. Cooper, "Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo," The EMBO Journal, 11[4]:1373-82, 1992. (the-scientist.com)
  • Was this a function of differences in receptor primary sequence, their locations in the cell, or, possibly, the specificity of the protein kinase domain of the receptor? (the-scientist.com)
  • By analyzing specific amino acid mutations of the α 2A - receptor with respect to changes in PB binding, certain sites were identified that may serve as the molecular target for phenoxybenzamine-mediated receptor blockade. (pharmacology2000.com)
  • For example, if a particular cysteine residue located in the TM3 domain was changed to valine (by mutation), the receptor becomes resistant to phenoxybenzamine inactivation. (pharmacology2000.com)
  • Results DIM, but not I3C, increased adipocyte differentiation through upregulation of peroxisome proliferator‐activated receptor γ and CCAAT/enhancer‐binding protein α. (researchgate.net)
  • Both domains were initially identified as modules that recognize phosphorylated tyrosines in receptor tyrosine kinases and other signaling proteins. (chemdiv.com)
  • Involvement of SH2-containing phosphotyrosine phosphatase Syp in erythropoietin receptor signal transduction pathways. (drugbank.com)
  • After synthesis, the single chain INS R precursor is glycosylated, dimerized and transported to the Golgi apparatus where it is processed at a furin-cleavage site within the middle fibronectin type III domain to generate the mature disulfide-linked alpha 2 beta 2 tetrameric receptor. (rndsystems.com)
  • When GFLs bind with GFRα, they form complexes and associate with the RET receptor, subsequently activating downstream signaling. (medsci.org)
  • A PDGF receptor domain essential for mitogenesis but not for many other responses to PDGF. (wikidata.org)
  • Three loops surround the peptide binding pocket and are important for specificity: Because these loops can be flexible, considerable variation in peptide binding can apply for any given SH2 domain. (eu.org)
  • Multiple modes of peptide recognition by the PTB domain of the cell fate determinant Numb. (sdbonline.org)
  • Our results suggest that a screening approach using protein crystallography is particularly useful to identify universal fragments for the conserved hydrophilic recognition sites found in target families such as SH2 domains, phosphatases, kinases, proteases, and esterases. (rcsb.org)
  • The discovery of phosphotyrosine phosphatases that contain SH2 domains suggests roles for these molecules in growth factor signaling pathways. (drugbank.com)
  • These conserved regions appear to contain those structural elements needed for recognizing and binding various endogenous hormone/neurotransmitters (e.g. norepinephrine and epinephrine) as well as other ligands. (pharmacology2000.com)
  • they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. (umbc.edu)
  • SH2 (Src homology region 2) and PTB (phosphotyrosine-binding) domains are small protein modules that mediate protein-protein interactions involved in many signal transduction pathways. (chemdiv.com)
  • The Src Homology 2 (SH2) domain is a major protein interaction module that is central to tyrosine kinase signaling. (eu.org)
  • Numb-associated kinase interacts with the phosphotyrosine binding domain of Numb and antagonizes the function of Numb in vivo. (sdbonline.org)
  • 1] J. Schlessinger and M. A. Lemmon, "SH2 and PTB domains in tyrosine kinase signaling. (chemdiv.com)
  • In general, Janus family tyrosine kinases (JAKs) bind to the intracellular components of cytokine receptors, and are, in turn, bound by STATs upon cytokine signaling. (medscape.com)
  • The addition of an affinity tag allowed us to avoid the use of antibodies targeted toward the intracellular C-terminal tail of APP, a region to which a number of reported interacting proteins bind ( King and Turner, 2004 ). (jneurosci.org)
  • There are actually three human α 2 -adrenoreceptor subtypes and the amino acid sequences between them are highly conserved within the seven hydrophobic TM domains. (pharmacology2000.com)
  • Znf domains are often found in clusters, where fingers can have different binding specificities. (embl-heidelberg.de)
  • Different growth factor receptors were known to bind different constellations of SH2 domain-containing proteins. (the-scientist.com)
  • that is, of the 182 amino acids defining the TM domains of the human α 2A -adrenergic receptors, about 40% are identical with the human β 2 -adrenergic receptors. (pharmacology2000.com)
  • The screen for new phospho-tyrosine mimics binding to the SH2 domain of (pp60)src was initiated because of the limited cell penetration of phosphates. (rcsb.org)
  • The chromo-domain binds histone H3 tails methylated on lysine 9. (cipsm.de)
  • Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). (wikipedia.org)
  • Human tensin has actin-binding sites, an SH2 (Pfam PF00017) domain and a region similar to the tumour suppressor PTEN. (wikipedia.org)
  • In NCK SH2 domains, the EF loop is positioned away from the BG loop, exposing the pY+3 binding pocket where the side chain of Val forms tight interactions. (eu.org)
  • Furthermore, structural analysis of particular TM domains suggested locations for phenoxybenzamine covalent interactions. (pharmacology2000.com)
  • No pairwise interactions are available for this conserved domain. (umbc.edu)
  • Subsequent studies have shown that, while binding of SH2 domains to their target proteins is strictly regulated by tyrosine phosphorylation, most PTB domains actually bind to their (nonphosphorylated) targets constitutively. (chemdiv.com)
  • From studies of APP trafficking and metabolism, the following pathways have emerged: in the first, a fraction of APP molecules residing on the cell surface are processed by ADAM/TACE "sheddases" N-terminal to the ectodomain-transmembrane domain to generate an 83 aa membrane-tethered stub, termed α-CTF. (jneurosci.org)
  • alternatively, APP molecules that are subject to endocytosis are proteolyzed by BACE1 at a site further N-terminal to the membrane domain to generate a 99 aa membrane-tethered stub, termed β-CTF. (jneurosci.org)
  • Through a novel CCM2 PTB domain - Smurf1 HECT domain interaction, CCM2 recruits Smurf1 to specific locations at the plasma membrane where it specifically degrades RhoA. (unc.edu)
  • TLN2 SH2 domains also bind phosphorylated tyrosines McCleverty CJ, Lin DC, Liddington RC (June 2007). (wikipedia.org)
  • The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) in the protein tensin tends to be found at the C-terminus. (wikipedia.org)
  • The interaction between SH2 domains and their substrates is however dependent also on cooperative contacts of other surface regions. (eu.org)
  • The RING domain is a protein interaction domain that has been implicated in a range of diverse biological processes. (embl-heidelberg.de)
  • The phosphate group of Tyr is tightly bound in the conserved pTyr binding pocket. (eu.org)
  • The N-terminal region is most conserved and contains the pTyr binding pocket. (eu.org)
  • These proteins contain two related domains known as the chromo- and the chromoshadow-domain. (cipsm.de)
  • The resulting phosphotyrosines attract STAT proteins, such as the STAT1 and STAT2 shown here (dark blue, dark green), which bind via their SH2 domains and become phosphorylated on specific phosphotyrosines, indicated here as Y's (inset), by the Jaks. (shu.edu)
  • Phosphorylated STATs dimerize within the cytosol via their phosphotyrosines and Src-homology 2 (SH2) domains. (medscape.com)
  • Thereafter, the STATs dimerize, each using its SH2 domain to bind to the phosphotyrosine of its partner, and then translocate to the nucleus, where they operate as transcription factors to activate expression of key genes, for example, the gene encoding an interferon. (shu.edu)
  • Direct binding between Syp and Grb2 was also observed in vitro. (drugbank.com)
  • Src Homology 2 (SH2) domains are small modular domains found within a great number of proteins involved in different signalling pathways. (eu.org)
  • The functions of SH2 and PTB domains include targeting of their host proteins to different cellular compartments, assembly of key components of signaling pathways in response to extracellular signals, and the control of autoinhibition, activation and dimerization of their host proteins. (chemdiv.com)
  • The large INS R extracellular domain is organized into two successive homologous globular domains, which are separated by a Cysteine-rich domain, followed by three fibronectin type III domains. (rndsystems.com)
  • As the main component, extracellular structure contains some cysteine-rich repeats domains marked as D1-D2-D3 in GFRα1-3, and D2-D3 in GFRα4 ( Figure 1 a ). (medsci.org)
  • No correlation between affinity and fragment binding was found for these polar fragments and hence affinity-based screening would have overlooked some interesting starting points for inhibitor design. (rcsb.org)
  • We found that Syp, a phosphotyrosine phosphatase, widely expressed in all tissues in mammals became phosphorylated on tyrosine after stimulation with Epo in M07ER cells engineered to express high levels of human EpoR. (drugbank.com)
  • Recently, Np95 (also known as UHRF1 or ICBP90) has been found to interact with Dnmt1 and to bind hemimethylated DNA, indicating together with genetic studies a central role in the maintenance of DNA methylation. (cipsm.de)
  • The histograms below the weblogo indicate mutations found on the domain. (umbc.edu)
  • PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. (umbc.edu)
  • Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. (embl-heidelberg.de)
  • PSPN not only binds GFRα4 but also signals in neurons mediated by GFRα1 [ 5 ]. (medsci.org)
  • Mutation of either Tyr740 or 751 strongly reduced binding of an SH2 protein. (the-scientist.com)
  • Mutations identified in many SH2 domain-containing proteins as well as the SH2 domain itself are associated with human diseases ranging from cancers, diabetes, to immunodeficiencies. (eu.org)
  • Regardless of the need for Th2 cells and their connected cytokines in the pathogenesis of sensitive respiratory disease, research of antigens regarded as causes of T-cell reactions have up to now been mostly limited by those recognized to bind IgE antibodies (7, 8) and induce IgE-mediated instant hypersensitivity reactions (9). (enmd-2076.com)
  • After binding its hormone FSH, FSHR undergoes internalization to very early endosomes (VEEs) for its acute signaling and sorting to a rapid recycling pathway. (frontiersin.org)
  • the E-value for the RING domain shown below is 8.69e-5. (embl.de)
  • the E-value for the RING domain shown below is 1.9e-1. (embl.de)
  • Dimerized STATs then translocate to the nucleus, where they bind DNA in the promoter sequences of target genes to activate transcription. (medscape.com)
  • We also characterize CCM2 as a Smurf1 binding partner. (unc.edu)