3maz
From Proteopedia
Crystal Structure of the Human BRDG1/STAP-1 SH2 Domain in Complex with the NTAL pTyr136 Peptide
Structural highlights
Disease[NTAL_HUMAN] Williams syndrome. Note=LAT2 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of LAT2 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.[1] [2] [3] Function[STAP1_HUMAN] In BCR signaling, appears to function as a docking protein acting downstream of TEC and participates in a positive feedback loop by increasing the activity of TEC.[4] [NTAL_HUMAN] Involved in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. May also be involved in BCR (B-cell antigen receptor)-mediated signaling in B-cells and FCGR1 (high affinity immunoglobulin gamma Fc receptor I)-mediated signaling in myeloid cells. Couples activation of these receptors and their associated kinases with distal intracellular events through the recruitment of GRB2.[5] [6] [7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCellular functions require specific protein-protein interactions that are often mediated by modular domains that use binding pockets to engage particular sequence motifs in their partners. Yet, how different members of a domain family select for distinct sequence motifs is not fully understood. The human genome encodes 120 Src homology 2 (SH2) domains (in 110 proteins), which mediate protein-protein interactions by binding to proteins with diverse phosphotyrosine (pTyr)-containing sequences. The structure of the SH2 domain of BRDG1 bound to a peptide revealed a binding pocket that was blocked by a loop residue in most other SH2 domains. Analysis of 63 SH2 domain structures suggested that the SH2 domains contain three binding pockets, which exhibit selectivity for the three positions after the pTyr in a peptide, and that SH2 domain loops defined the accessibility and shape of these pockets. Despite sequence variability in the loops, we identified conserved structural features in the loops of SH2 domains responsible for controlling access to these surface pockets. We engineered new loops in an SH2 domain that altered specificity as predicted. Thus, selective blockage of binding subsites or pockets by surface loops provides a molecular basis by which the diverse modes of ligand recognition by the SH2 domain may have evolved and provides a framework for engineering SH2 domains and designing SH2-specific inhibitors. Loops govern SH2 domain specificity by controlling access to binding pockets.,Kaneko T, Huang H, Zhao B, Li L, Liu H, Voss CK, Wu C, Schiller MR, Li SS Sci Signal. 2010 May 4;3(120):ra34. PMID:20442417[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Huang, H | Kaneko, T | Li, L | Li, S S | Liu, H | Schiller, M R | Voss, C K | Wu, C | Zhao, B | Cytoplasm | Modular domain | Phosphoprotein | Phosphotyrosine | Sh2 domain | Signaling protein | Specificity
