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| - | [[Image:1i3z.gif|left|200px]] | |
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| - | {{Structure
| + | ==MURINE EAT2 SH2 DOMAIN IN COMPLEX WITH SLAM PHOSPHOPEPTIDE== |
| - | |PDB= 1i3z |SIZE=350|CAPTION= <scene name='initialview01'>1i3z</scene>, resolution 2.15Å
| + | <StructureSection load='1i3z' size='340' side='right'caption='[[1i3z]], [[Resolution|resolution]] 2.15Å' scene=''> |
| - | |SITE=
| + | == Structural highlights == |
| - | |LIGAND=
| + | <table><tr><td colspan='2'>[[1i3z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1I3Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1I3Z FirstGlance]. <br> |
| - | |ACTIVITY= | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15Å</td></tr> |
| - | |GENE=
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></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=1i3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1i3z OCA], [https://pdbe.org/1i3z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1i3z RCSB], [https://www.ebi.ac.uk/pdbsum/1i3z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1i3z ProSAT]</span></td></tr> |
| - | | + | </table> |
| - | '''MURINE EAT2 SH2 DOMAIN IN COMPLEX WITH SLAM PHOSPHOPEPTIDE''' | + | == Function == |
| - | | + | [https://www.uniprot.org/uniprot/SH21B_MOUSE SH21B_MOUSE] Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as CD84, SLAMF1, LY9 and CD244. In SLAM signaling seems to cooperate with SH2D1A/SAP. Plays a role in regulation of effector functions of natural killer (NK) cells by controlling signal transduction through CD244/2B4. However, conflicting results are reported which may reflect the use of different strain backgrounds. Proposed to act as an inhibitor of CD244-mediated NK cell function including cytotoxicity and IFN-gamma production, the latter found also by triggering KLRA4 and KLRK1 next to CD244 (PubMed:16127454). Seems to positively regulate CD244- and CD84-dependent NK cell functions implicating CD244-mediated phosphorylation of VAV1. Activation of SLAMF7-mediated NK cell function does not effect receptor tyrosine phosphorylation but distal signaling (PubMed:19151721, PubMed:20962259, PubMed:24687958). In the context of NK cell-mediated cytotoxicity does not enhance conjugate formation with target cells but stimulates polarization of the microtubule-organizing center and cytotoxic granules toward the NK cell synapse (PubMed:24687958). Negatively regulates CD40-induced cytokine production in dendritic cells downstream of SLAM family receptors probably by inducing activation of the PI3K pathway to inhibit p38 MAPK and JNK activation (PubMed:26432891).[UniProtKB:O14796]<ref>PMID:16127454</ref> <ref>PMID:19151721</ref> <ref>PMID:20962259</ref> <ref>PMID:24687958</ref> <ref>PMID:26432891</ref> |
| - | | + | == Evolutionary Conservation == |
| - | ==Overview== | + | [[Image:Consurf_key_small.gif|200px|right]] |
| - | The T and natural killer (NK) cell-specific gene SAP (SH2D1A) encodes a 'free SH2 domain' that binds a specific tyrosine motif in the cytoplasmic tail of SLAM (CD150) and related cell surface proteins. Mutations in SH2D1A cause the X-linked lymphoproliferative disease, a primary immunodeficiency. Here we report that a second gene encoding a free SH2 domain, EAT-2, is expressed in macrophages and B lympho cytes. The EAT-2 structure in complex with a phosphotyrosine peptide containing a sequence motif with Tyr281 of the cytoplasmic tail of CD150 is very similar to the structure of SH2D1A complexed with the same peptide. This explains the high affinity of EAT-2 for the pTyr motif in the cytoplasmic tail of CD150 but, unlike SH2D1A, EAT-2 does not bind to non-phosphorylated CD150. EAT-2 binds to the phosphorylated receptors CD84, CD150, CD229 and CD244, and acts as a natural inhibitor, which interferes with the recruitment of the tyrosine phosphatase SHP-2. We conclude that EAT-2 plays a role in controlling signal transduction through at least four receptors expressed on the surface of professional antigen-presenting cells.
| + | Check<jmol> |
| - | | + | <jmolCheckbox> |
| - | ==About this Structure== | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i3/1i3z_consurf.spt"</scriptWhenChecked> |
| - | 1I3Z is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1I3Z OCA].
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| - | | + | <text>to colour the structure by Evolutionary Conservation</text> |
| - | ==Reference== | + | </jmolCheckbox> |
| - | Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells., Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, Gullo C, Howie D, Rietdijk S, Thompson A, Coyle AJ, Denny C, Yaffe MB, Engel P, Eck MJ, Terhorst C, EMBO J. 2001 Nov 1;20(21):5840-52. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11689425 11689425]
| + | </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=1i3z ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Protein complex]]
| + | [[Category: Eck MJ]] |
| - | [[Category: Eck, M J.]] | + | [[Category: Lu J]] |
| - | [[Category: Lu, J.]] | + | [[Category: Morra M]] |
| - | [[Category: Morra, M.]] | + | [[Category: Poy F]] |
| - | [[Category: Poy, F.]] | + | [[Category: Terhorst C]] |
| - | [[Category: Terhorst, C.]] | + | |
| - | [[Category: sh2 domain phosphotyrosine signal transduction lymphocyte]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 11:45:15 2008''
| + | |
| Structural highlights
Function
SH21B_MOUSE Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as CD84, SLAMF1, LY9 and CD244. In SLAM signaling seems to cooperate with SH2D1A/SAP. Plays a role in regulation of effector functions of natural killer (NK) cells by controlling signal transduction through CD244/2B4. However, conflicting results are reported which may reflect the use of different strain backgrounds. Proposed to act as an inhibitor of CD244-mediated NK cell function including cytotoxicity and IFN-gamma production, the latter found also by triggering KLRA4 and KLRK1 next to CD244 (PubMed:16127454). Seems to positively regulate CD244- and CD84-dependent NK cell functions implicating CD244-mediated phosphorylation of VAV1. Activation of SLAMF7-mediated NK cell function does not effect receptor tyrosine phosphorylation but distal signaling (PubMed:19151721, PubMed:20962259, PubMed:24687958). In the context of NK cell-mediated cytotoxicity does not enhance conjugate formation with target cells but stimulates polarization of the microtubule-organizing center and cytotoxic granules toward the NK cell synapse (PubMed:24687958). Negatively regulates CD40-induced cytokine production in dendritic cells downstream of SLAM family receptors probably by inducing activation of the PI3K pathway to inhibit p38 MAPK and JNK activation (PubMed:26432891).[UniProtKB:O14796][1] [2] [3] [4] [5]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Roncagalli R, Taylor JE, Zhang S, Shi X, Chen R, Cruz-Munoz ME, Yin L, Latour S, Veillette A. Negative regulation of natural killer cell function by EAT-2, a SAP-related adaptor. Nat Immunol. 2005 Oct;6(10):1002-10. PMID:16127454 doi:10.1038/ni1242
- ↑ Cruz-Munoz ME, Dong Z, Shi X, Zhang S, Veillette A. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat Immunol. 2009 Mar;10(3):297-305. PMID:19151721 doi:10.1038/ni.1693
- ↑ Wang N, Calpe S, Westcott J, Castro W, Ma C, Engel P, Schatzle JD, Terhorst C. Cutting edge: The adapters EAT-2A and -2B are positive regulators of CD244 CD84-dependent NK cell functions in the C57BL/6 mouse. J Immunol. 2010 Nov 15;185(10):5683-7. PMID:20962259 doi:10.4049/jimmunol.1001974
- ↑ Perez-Quintero LA, Roncagalli R, Guo H, Latour S, Davidson D, Veillette A. EAT-2, a SAP-like adaptor, controls NK cell activation through phospholipase Cgamma, Ca++, and Erk, leading to granule polarization. J Exp Med. 2014 Apr 7;211(4):727-42. doi: 10.1084/jem.20132038. Epub 2014 Mar 31. PMID:24687958 doi:http://dx.doi.org/10.1084/jem.20132038
- ↑ Talaei N, Yu T, Manion K, Bremner R, Wither JE. Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling. J Immunol. 2015 Nov 15;195(10):4623-31. PMID:26432891 doi:10.4049/jimmunol.1500552
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