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1ka7

From Proteopedia

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Current revision

SAP/SH2D1A bound to peptide n-Y-c

Structural highlights

1ka7 is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SH21A_HUMAN Defects in SH2D1A are a cause of lymphoproliferative syndrome X-linked type 1 (XLP1) [MIM:308240; also known as X-linked lymphoproliferative disease (XLPD) or Duncan disease. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

Function

SH21A_HUMAN Inhibitor of the SLAM self-association. Acts by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region. Mediates interaction between FYN and SLAMF1. May also regulate the activity of the neurotrophin receptors NTRK1, NTRK2 and NTRK3.

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 PubMed

The SH2 domain protein SAP/SH2D1A, encoded by the X-linked lymphoproliferative (XLP) syndrome gene, associates with the hematopoietic cell surface receptor SLAM in a phosphorylation-independent manner. By screening a repertoire of synthetic peptides, the specificity of SAP/SH2D1A has been mapped and a consensus sequence motif for binding identified, T/S-x-x-x-x-V/I, where x represents any amino acid. Remarkably, this motif contains neither a Tyr nor a pTyr residue, a hallmark of conventional SH2 domain-ligand interactions. The structures of the protein, determined by NMR, in complex with two distinct peptides provide direct evidence in support of a "three-pronged" binding mechanism for the SAP/SH2D1A SH2 domain in contrast to the "two-pronged" binding for conventional SH2 domains. Differences in the structures of the two complexes suggest considerable flexibility in the SH2 domain, as further confirmed and characterized by hydrogen exchange studies. The structures also explain binding defects observed in disease-causing SAP/SH2D1A mutants and suggest that phosphorylation-independent interactions mediated by SAP/SH2D1A likely play an important role in the pathogenesis of XLP.

A "three-pronged" binding mechanism for the SAP/SH2D1A SH2 domain: structural basis and relevance to the XLP syndrome.,Hwang PM, Li C, Morra M, Lillywhite J, Muhandiram DR, Gertler F, Terhorst C, Kay LE, Pawson T, Forman-Kay JD, Li SC EMBO J. 2002 Feb 1;21(3):314-23. PMID:11823424^[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Morra M, Simarro-Grande M, Martin M, Chen AS, Lanyi A, Silander O, Calpe S, Davis J, Pawson T, Eck MJ, Sumegi J, Engel P, Li SC, Terhorst C. Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients. J Biol Chem. 2001 Sep 28;276(39):36809-16. Epub 2001 Jul 26. PMID:11477068 doi:10.1074/jbc.M101305200
↑ Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, Cahn AP, Durham J, Heath P, Wray P, Pavitt R, Wilkinson J, Leversha M, Huckle E, Shaw-Smith CJ, Dunham A, Rhodes S, Schuster V, Porta G, Yin L, Serafini P, Sylla B, Zollo M, Franco B, Bolino A, Seri M, Lanyi A, Davis JR, Webster D, Harris A, Lenoir G, de St Basile G, Jones A, Behloradsky BH, Achatz H, Murken J, Fassler R, Sumegi J, Romeo G, Vaudin M, Ross MT, Meindl A, Bentley DR. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet. 1998 Oct;20(2):129-35. PMID:9771704 doi:10.1038/2424
↑ Hwang PM, Li C, Morra M, Lillywhite J, Muhandiram DR, Gertler F, Terhorst C, Kay LE, Pawson T, Forman-Kay JD, Li SC. A "three-pronged" binding mechanism for the SAP/SH2D1A SH2 domain: structural basis and relevance to the XLP syndrome. EMBO J. 2002 Feb 1;21(3):314-23. PMID:11823424 doi:10.1093/emboj/21.3.314
↑ Yin L, Ferrand V, Lavoue MF, Hayoz D, Philippe N, Souillet G, Seri M, Giacchino R, Castagnola E, Hodgson S, Sylla BS, Romeo G. SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients. Hum Genet. 1999 Nov;105(5):501-5. PMID:10598819
↑ Sumegi J, Huang D, Lanyi A, Davis JD, Seemayer TA, Maeda A, Klein G, Seri M, Wakiguchi H, Purtilo DT, Gross TG. Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood. 2000 Nov 1;96(9):3118-25. PMID:11049992
↑ Benoit L, Wang X, Pabst HF, Dutz J, Tan R. Defective NK cell activation in X-linked lymphoproliferative disease. J Immunol. 2000 Oct 1;165(7):3549-53. PMID:11034354
↑ Sumazaki R, Kanegane H, Osaki M, Fukushima T, Tsuchida M, Matsukura H, Shinozaki K, Kimura H, Matsui A, Miyawaki T. SH2D1A mutations in Japanese males with severe Epstein-Barr virus--associated illnesses. Blood. 2001 Aug 15;98(4):1268-70. PMID:11493483
↑ Li C, Iosef C, Jia CY, Gkourasas T, Han VK, Shun-Cheng Li S. Disease-causing SAP mutants are defective in ligand binding and protein folding. Biochemistry. 2003 Dec 23;42(50):14885-92. PMID:14674764 doi:10.1021/bi034798l
↑ Erdos M, Uzvolgyi E, Nemes Z, Torok O, Rakoczi E, Went-Sumegi N, Sumegi J, Marodi L. Characterization of a new disease-causing mutation of SH2D1A in a family with X-linked lymphoproliferative disease. Hum Mutat. 2005 May;25(5):506. PMID:15841490 doi:10.1002/humu.9339
↑ Hare NJ, Ma CS, Alvaro F, Nichols KE, Tangye SG. Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP. Int Immunol. 2006 Jul;18(7):1055-65. Epub 2006 May 23. PMID:16720617 doi:dxl039
↑ Hwang PM, Li C, Morra M, Lillywhite J, Muhandiram DR, Gertler F, Terhorst C, Kay LE, Pawson T, Forman-Kay JD, Li SC. A "three-pronged" binding mechanism for the SAP/SH2D1A SH2 domain: structural basis and relevance to the XLP syndrome. EMBO J. 2002 Feb 1;21(3):314-23. PMID:11823424 doi:10.1093/emboj/21.3.314

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1ka7"

@@ Line 1: / Line 1: @@
 ==SAP/SH2D1A bound to peptide n-Y-c==
-<StructureSection load='1ka7' size='340' side='right' caption='[[1ka7]], [[NMR_Ensembles_of_Models | 1 NMR models]]' scene=''>
+<StructureSection load='1ka7' size='340' side='right'caption='[[1ka7]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1ka7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KA7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1KA7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1ka7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KA7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1KA7 FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ka6|1ka6]]</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ka7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ka7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1ka7 RCSB], [http://www.ebi.ac.uk/pdbsum/1ka7 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ka7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ka7 OCA], [https://pdbe.org/1ka7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ka7 RCSB], [https://www.ebi.ac.uk/pdbsum/1ka7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ka7 ProSAT]</span></td></tr>
-<table>
+</table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/SH21A_HUMAN SH21A_HUMAN]] Defects in SH2D1A are a cause of lymphoproliferative syndrome X-linked type 1 (XLP1) [MIM:[http://omim.org/entry/308240 308240]]; also known as X-linked lymphoproliferative disease (XLPD) or Duncan disease. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:11477068</ref> <ref>PMID:9771704</ref> <ref>PMID:11823424</ref> <ref>PMID:10598819</ref> <ref>PMID:11049992</ref> <ref>PMID:11034354</ref> <ref>PMID:11493483</ref> <ref>PMID:14674764</ref> <ref>PMID:15841490</ref> <ref>PMID:16720617</ref>
+[https://www.uniprot.org/uniprot/SH21A_HUMAN SH21A_HUMAN] Defects in SH2D1A are a cause of lymphoproliferative syndrome X-linked type 1 (XLP1) [MIM:[https://omim.org/entry/308240 308240]; also known as X-linked lymphoproliferative disease (XLPD) or Duncan disease. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:11477068</ref> <ref>PMID:9771704</ref> <ref>PMID:11823424</ref> <ref>PMID:10598819</ref> <ref>PMID:11049992</ref> <ref>PMID:11034354</ref> <ref>PMID:11493483</ref> <ref>PMID:14674764</ref> <ref>PMID:15841490</ref> <ref>PMID:16720617</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/SH21A_HUMAN SH21A_HUMAN]] Inhibitor of the SLAM self-association. Acts by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region. Mediates interaction between FYN and SLAMF1. May also regulate the activity of the neurotrophin receptors NTRK1, NTRK2 and NTRK3. [[http://www.uniprot.org/uniprot/SLAF1_HUMAN SLAF1_HUMAN]] High-affinity self-ligand important in bidirectional T-cell to B-cell stimulation. SLAM-induced signal-transduction events in T-lymphocytes are different from those in B-cells. Two modes of SLAM signaling are likely to exist: one in which the inhibitor SH2D1A acts as a negative regulator and another in which protein-tyrosine phosphatase 2C (PTPN11)-dependent signal transduction operates.
+[https://www.uniprot.org/uniprot/SH21A_HUMAN SH21A_HUMAN] Inhibitor of the SLAM self-association. Acts by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region. Mediates interaction between FYN and SLAMF1. May also regulate the activity of the neurotrophin receptors NTRK1, NTRK2 and NTRK3.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ka/1ka7_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ka/1ka7_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ka7 ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 28: / Line 29: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 1ka7" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
@@ Line 33: / Line 35: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Forman-Kay, J.]]
+[[Category: Large Structures]]
-[[Category: Gertler, F.]]
+[[Category: Forman-Kay J]]
-[[Category: Hwang, P M.]]
+[[Category: Gertler F]]
-[[Category: Kay, L E.]]
+[[Category: Hwang PM]]
-[[Category: Li, C.]]
+[[Category: Kay LE]]
-[[Category: Li, S C.]]
+[[Category: Li C]]
-[[Category: Lillywhite, J.]]
+[[Category: Li S-C]]
-[[Category: Morra, M.]]
+[[Category: Lillywhite J]]
-[[Category: Pawson, T.]]
+[[Category: Morra M]]
-[[Category: Terhorst, C.]]
+[[Category: Pawson T]]
-[[Category: Immune system]]
+[[Category: Terhorst C]]
-[[Category: Protein-peptide complex]]
-[[Category: Sh2 domain]]

1ka7

From Proteopedia

Current revision

SAP/SH2D1A bound to peptide n-Y-c

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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