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| | <StructureSection load='4jfh' size='340' side='right'caption='[[4jfh]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='4jfh' size='340' side='right'caption='[[4jfh]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4jfh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JFH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JFH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4jfh]] is a 2 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=4JFH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JFH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jfd|4jfd]], [[4jfe|4jfe]], [[4jff|4jff]], [[4jfo|4jfo]], [[4jfp|4jfp]], [[4jfq|4jfq]]</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=4jfh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jfh OCA], [https://pdbe.org/4jfh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jfh RCSB], [https://www.ebi.ac.uk/pdbsum/4jfh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jfh ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4jfh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jfh OCA], [http://pdbe.org/4jfh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jfh RCSB], [http://www.ebi.ac.uk/pdbsum/4jfh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jfh 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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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[T-cell receptor|T-cell receptor]] | + | *[[T-cell receptor 3D structures|T-cell receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Cole, D K]] | + | [[Category: Cole DK]] |
| - | [[Category: Madura, F]] | + | [[Category: Madura F]] |
| - | [[Category: Rizkallah, P J]] | + | [[Category: Rizkallah PJ]] |
| - | [[Category: Sewell, A K]] | + | [[Category: Sewell AK]] |
| - | [[Category: High affinity]]
| + | |
| - | [[Category: Hla]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Immunoglobulin]]
| + | |
| - | [[Category: Melanoma]]
| + | |
| - | [[Category: Tcr]]
| + | |
| 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
The T-cell receptor (TCR) recognises peptides bound to major histocompatibility molecules (pMHC) and allows T-cells to interrogate the cellular proteaome for internal anomalies from the cell surface. The TCR contacts both MHC and peptide in an interaction characterised by weak affinity (KD >1 muM). We used phage-display to produce a melanoma-specific TCR (alpha24beta17) with a >30,000-fold enhanced binding affinity (KD = 600 pM) in order to aid our exploration of the molecular mechanisms utilised to maintain peptide specificity. Remarkably, although the enhanced affinity was mediated primarily through new TCR-MHC contacts, alpha24beta17 remained acutely sensitive to modifications at every position along the peptide backbone, mimicking the specificity of the wild type TCR. Thermodynamic analyses revealed an important role for solvation in directing peptide specificity. These findings advance our understanding of the molecular mechanisms that can govern the exquisite peptide specificity characteristic of TCR recognition.
T-cell receptor specificity maintained by altered thermodynamics.,Madura F, Rizkallah PJ, Miles KM, Holland CJ, Bulek AM, Fuller A, Schauenburg AJ, Miles JJ, Liddy N, Sami M, Li Y, Hossain M, Baker BM, Jakobsen BK, Sewell AK, Cole DK J Biol Chem. 2013 May 22. PMID:23698002[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
- ↑ Madura F, Rizkallah PJ, Miles KM, Holland CJ, Bulek AM, Fuller A, Schauenburg AJ, Miles JJ, Liddy N, Sami M, Li Y, Hossain M, Baker BM, Jakobsen BK, Sewell AK, Cole DK. T-cell receptor specificity maintained by altered thermodynamics. J Biol Chem. 2013 May 22. PMID:23698002 doi:10.1074/jbc.M113.464560
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