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[[Image:1d1z.gif|left|200px]]<br /><applet load="1d1z" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1d1z, resolution 1.4&Aring;" />
'''CRYSTAL STRUCTURE OF THE XLP PROTEIN SAP'''<br />


==Overview==
==CRYSTAL STRUCTURE OF THE XLP PROTEIN SAP==
SAP, the product of the gene mutated in X-linked lymphoproliferative syndrome (XLP), consists of a single SH2 domain that has been shown to bind the cytoplasmic tail of the lymphocyte coreceptor SLAM. Here we describe structures that show that SAP binds phosphorylated and nonphosphorylated SLAM peptides in a similar mode, with the tyrosine or phosphotyrosine residue inserted into the phosphotyrosine-binding pocket. We find that specific interactions with residues N-terminal to the tyrosine, in addition to more characteristic C-terminal interactions, stabilize the complexes. A phosphopeptide library screen and analysis of mutations identified in XLP patients confirm that these extended interactions are required for SAP function. Further, we show that SAP and the similar protein EAT-2 recognize the sequence motif TIpYXX(V/I).
<StructureSection load='1d1z' size='340' side='right'caption='[[1d1z]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
 
== Structural highlights ==
==Disease==
<table><tr><td colspan='2'>[[1d1z]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D1Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1D1Z FirstGlance]. <br>
Known diseases associated with this structure: Amyloidosis, secondary, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104770 104770]], Lymphoproliferative syndrome, X-linked OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300490 300490]]
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4&#8491;</td></tr>
 
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
==About this Structure==
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1d1z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d1z OCA], [https://pdbe.org/1d1z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1d1z RCSB], [https://www.ebi.ac.uk/pdbsum/1d1z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1d1z ProSAT]</span></td></tr>
1D1Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D1Z OCA].  
</table>
 
== Disease ==
==Reference==
[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>
Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition., Poy F, Yaffe MB, Sayos J, Saxena K, Morra M, Sumegi J, Cantley LC, Terhorst C, Eck MJ, Mol Cell. 1999 Oct;4(4):555-61. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10549287 10549287]
== Function ==
[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/d1/1d1z_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/main_output.php?pdb_ID=1d1z ConSurf].
<div style="clear:both"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Eck, M J.]]
[[Category: Eck MJ]]
[[Category: Poy, F.]]
[[Category: Poy F]]
[[Category: Saxena, K.]]
[[Category: Saxena K]]
[[Category: Sayos, J.]]
[[Category: Sayos J]]
[[Category: Yaffe, M B.]]
[[Category: Yaffe MB]]
[[Category: SO4]]
[[Category: sh2 domains]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:12:18 2008''

Latest revision as of 09:48, 7 February 2024

CRYSTAL STRUCTURE OF THE XLP PROTEIN SAPCRYSTAL STRUCTURE OF THE XLP PROTEIN SAP

Structural highlights

1d1z is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.4Å
Ligands:
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.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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

1d1z, resolution 1.40Å

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