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| | <StructureSection load='3qeu' size='340' side='right'caption='[[3qeu]], [[Resolution|resolution]] 2.09Å' scene=''> | | <StructureSection load='3qeu' size='340' side='right'caption='[[3qeu]], [[Resolution|resolution]] 2.09Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3qeu]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QEU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QEU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3qeu]] 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=3QEU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QEU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LI:LITHIUM+ION'>LI</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.09Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qdg|3qdg]], [[3qdj|3qdj]], [[3qdm|3qdm]], [[3qeq|3qeq]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LI:LITHIUM+ION'>LI</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=3qeu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qeu OCA], [https://pdbe.org/3qeu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qeu RCSB], [https://www.ebi.ac.uk/pdbsum/3qeu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qeu ProSAT]</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=3qeu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qeu OCA], [https://pdbe.org/3qeu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qeu RCSB], [https://www.ebi.ac.uk/pdbsum/3qeu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qeu ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/TRAC_HUMAN TRAC_HUMAN] TCR-alpha-beta-positive T-cell deficiency. The disease is caused by variants affecting the gene represented in this entry. |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TRAC_HUMAN TRAC_HUMAN] Constant region of T cell receptor (TR) alpha chain (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).<ref>PMID:15040585</ref> <ref>PMID:23524462</ref> <ref>PMID:24600447</ref> <ref>PMID:25493333</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Baker, B M]] | + | [[Category: Baker BM]] |
| - | [[Category: Borbulevych, O Y]] | + | [[Category: Borbulevych OY]] |
| - | [[Category: Santhanagopolan, S M]] | + | [[Category: Santhanagopolan SM]] |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Cross-reactivity]]
| + | |
| - | [[Category: Hla-a2]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Mart-1 peptide]]
| + | |
| - | [[Category: Melanoma]]
| + | |
| - | [[Category: Mhc class i]]
| + | |
| - | [[Category: Nonapeptide]]
| + | |
| - | [[Category: Tcr dmf4]]
| + | |
| - | [[Category: Tcr dmf5]]
| + | |
| Structural highlights
Disease
TRAC_HUMAN TCR-alpha-beta-positive T-cell deficiency. The disease is caused by variants affecting the gene represented in this entry.
Function
TRAC_HUMAN Constant region of T cell receptor (TR) alpha chain (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).[1] [2] [3] [4]
Publication Abstract from PubMed
T cells engineered to express TCRs specific for tumor Ags can drive cancer regression. The first TCRs used in cancer gene therapy, DMF4 and DMF5, recognize two structurally distinct peptide epitopes of the melanoma-associated MART-1/Melan-A protein, both presented by the class I MHC protein HLA-A*0201. To help understand the mechanisms of TCR cross-reactivity and provide a foundation for the further development of immunotherapy, we determined the crystallographic structures of DMF4 and DMF5 in complex with both of the MART-1/Melan-A epitopes. The two TCRs use different mechanisms to accommodate the two ligands. Although DMF4 binds the two with a different orientation, altering its position over the peptide/MHC, DMF5 binds them both identically. The simpler mode of cross-reactivity by DMF5 is associated with higher affinity toward both ligands, consistent with the superior functional avidity of DMF5. More generally, the observation of two diverging mechanisms of cross-reactivity with the same Ags and the finding that TCR-binding orientation can be determined by peptide alone extend our understanding of the mechanisms underlying TCR cross-reactivity.
TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms.,Borbulevych OY, Santhanagopolan SM, Hossain M, Baker BM J Immunol. 2011 Jul 27. PMID:21795600[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nikolich-Zugich J, Slifka MK, Messaoudi I. The many important facets of T-cell repertoire diversity. Nat Rev Immunol. 2004 Feb;4(2):123-32. doi: 10.1038/nri1292. PMID:15040585 doi:http://dx.doi.org/10.1038/nri1292
- ↑ Brownlie RJ, Zamoyska R. T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol. 2013 Apr;13(4):257-69. doi: 10.1038/nri3403. PMID:23524462 doi:http://dx.doi.org/10.1038/nri3403
- ↑ Lefranc MP. Immunoglobulin and T Cell Receptor Genes: IMGT((R)) and the Birth and Rise of Immunoinformatics. Front Immunol. 2014 Feb 5;5:22. doi: 10.3389/fimmu.2014.00022. eCollection 2014. PMID:24600447 doi:http://dx.doi.org/10.3389/fimmu.2014.00022
- ↑ Rossjohn J, Gras S, Miles JJ, Turner SJ, Godfrey DI, McCluskey J. T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2015;33:169-200. doi: 10.1146/annurev-immunol-032414-112334., Epub 2014 Dec 10. PMID:25493333 doi:http://dx.doi.org/10.1146/annurev-immunol-032414-112334
- ↑ Borbulevych OY, Santhanagopolan SM, Hossain M, Baker BM. TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms. J Immunol. 2011 Jul 27. PMID:21795600 doi:10.4049/jimmunol.1101268
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