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| - | {{STRUCTURE_2ozo| PDB=2ozo | SCENE= }} | |
| - | ===Autoinhibited intact human ZAP-70=== | |
| - | {{ABSTRACT_PUBMED_17512407}} | |
| | | | |
| - | ==Disease== | + | ==Autoinhibited intact human ZAP-70== |
| - | [[http://www.uniprot.org/uniprot/ZAP70_HUMAN ZAP70_HUMAN]] Defects in ZAP70 are the cause of selective T-cell defect (STCD) [MIM:[http://omim.org/entry/269840 269840]]. A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T cells.<ref>PMID:8124727</ref><ref>PMID:8202713</ref><ref>PMID:11412303</ref><ref>PMID:11123350</ref><ref>PMID:18509675</ref> | + | <StructureSection load='2ozo' size='340' side='right'caption='[[2ozo]], [[Resolution|resolution]] 2.60Å' scene=''> |
| - | | + | == Structural highlights == |
| - | ==Function== | + | <table><tr><td colspan='2'>[[2ozo]] is a 1 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=2OZO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OZO FirstGlance]. <br> |
| - | [[http://www.uniprot.org/uniprot/ZAP70_HUMAN ZAP70_HUMAN]] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR).<ref>PMID:1423621</ref><ref>PMID:8124727</ref><ref>PMID:8702662</ref><ref>PMID:9489702</ref><ref>PMID:11353765</ref> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> |
| - | | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=2ozo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ozo OCA], [https://pdbe.org/2ozo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ozo RCSB], [https://www.ebi.ac.uk/pdbsum/2ozo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ozo ProSAT]</span></td></tr> |
| - | [[2ozo]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OZO OCA]. | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/ZAP70_HUMAN ZAP70_HUMAN] Defects in ZAP70 are the cause of selective T-cell defect (STCD) [MIM:[https://omim.org/entry/269840 269840]. A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T cells.<ref>PMID:8124727</ref> <ref>PMID:8202713</ref> <ref>PMID:11412303</ref> <ref>PMID:11123350</ref> <ref>PMID:18509675</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ZAP70_HUMAN ZAP70_HUMAN] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR).<ref>PMID:1423621</ref> <ref>PMID:8124727</ref> <ref>PMID:8702662</ref> <ref>PMID:9489702</ref> <ref>PMID:11353765</ref> |
| | + | == 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/oz/2ozo_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=2ozo ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Tyrosine kinase|Tyrosine kinase]] | + | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] |
| - | | + | == References == |
| - | ==Reference== | + | <references/> |
| - | <ref group="xtra">PMID:017512407</ref><references group="xtra"/><references/>
| + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific protein-tyrosine kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Brdicka, T.]] | + | [[Category: Brdicka T]] |
| - | [[Category: Cao, X.]] | + | [[Category: Cao X]] |
| - | [[Category: Deindl, S.]] | + | [[Category: Deindl S]] |
| - | [[Category: Kadlecek, T A.]] | + | [[Category: Kadlecek TA]] |
| - | [[Category: Kuriyan, J.]] | + | [[Category: Kuriyan J]] |
| - | [[Category: Weiss, A.]] | + | [[Category: Weiss A]] |
| - | [[Category: Autoinhibition]]
| + | |
| - | [[Category: Hydrogen bonding network]]
| + | |
| - | [[Category: Inactive zap-70]]
| + | |
| - | [[Category: Itam]]
| + | |
| - | [[Category: Tandem sh2]]
| + | |
| - | [[Category: Tcr signaling]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
ZAP70_HUMAN Defects in ZAP70 are the cause of selective T-cell defect (STCD) [MIM:269840. A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T cells.[1] [2] [3] [4] [5]
Function
ZAP70_HUMAN Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR).[6] [7] [8] [9] [10]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
See Also
References
- ↑ Arpaia E, Shahar M, Dadi H, Cohen A, Roifman CM. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell. 1994 Mar 11;76(5):947-58. PMID:8124727
- ↑ Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, Parslow TG, Weiss A. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science. 1994 Jun 10;264(5165):1599-601. PMID:8202713
- ↑ Toyabe S, Watanabe A, Harada W, Karasawa T, Uchiyama M. Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling. Immunology. 2001 Jun;103(2):164-71. PMID:11412303
- ↑ Elder ME, Skoda-Smith S, Kadlecek TA, Wang F, Wu J, Weiss A. Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70. J Immunol. 2001 Jan 1;166(1):656-61. PMID:11123350
- ↑ Turul T, Tezcan I, Artac H, de Bruin-Versteeg S, Barendregt BH, Reisli I, Sanal O, van Dongen JJ, van der Burg M. Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency. Eur J Pediatr. 2009 Jan;168(1):87-93. doi: 10.1007/s00431-008-0718-x. Epub 2008, May 29. PMID:18509675 doi:10.1007/s00431-008-0718-x
- ↑ Chan AC, Iwashima M, Turck CW, Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell. 1992 Nov 13;71(4):649-62. PMID:1423621
- ↑ Arpaia E, Shahar M, Dadi H, Cohen A, Roifman CM. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell. 1994 Mar 11;76(5):947-58. PMID:8124727
- ↑ Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J Biol Chem. 1996 Aug 16;271(33):19641-4. PMID:8702662
- ↑ Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell. 1998 Jan 9;92(1):83-92. PMID:9489702
- ↑ Wang HY, Altman Y, Fang D, Elly C, Dai Y, Shao Y, Liu YC. Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70. J Biol Chem. 2001 Jul 13;276(28):26004-11. Epub 2001 May 15. PMID:11353765 doi:10.1074/jbc.M010738200
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