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==XPA5 TCR in complex with HLA-DQ2-omega1==
<StructureSection load='7sg2' size='340' side='right'caption='[[7sg2]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7sg2]] is a 10 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=7SG2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SG2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=7sg2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sg2 OCA], [https://pdbe.org/7sg2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sg2 RCSB], [https://www.ebi.ac.uk/pdbsum/7sg2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sg2 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DQA1_HUMAN DQA1_HUMAN] Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal miroenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.
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== Publication Abstract from PubMed ==
Celiac disease is a T cell-mediated chronic inflammatory condition often characterized by human leukocyte antigen (HLA)-DQ2.5 molecules presenting gluten epitopes derived from wheat, barley, and rye. Although some T cells exhibit cross-reactivity toward distinct gluten epitopes, the structural basis underpinning such cross-reactivity is unclear. Here, we investigated the T-cell receptor specificity and cross-reactivity of two immunodominant wheat gluten epitopes, DQ2.5-glia-alpha1a (PFPQPELPY) and DQ2.5-glia-omega1 (PFPQPEQPF). We show by surface plasmon resonance that a T-cell receptor alpha variable (TRAV) 4(+)-T-cell receptor beta variable (TRBV) 29-1(+) TCR bound to HLA-DQ2.5-glia-alpha1a and HLA-DQ2.5-glia-omega1 with similar affinity, whereas a TRAV4(-) (TRAV9-2(+)) TCR recognized HLA-DQ2.5-glia-omega1 only. We further determined the crystal structures of the TRAV4(+)-TRBV29-1(+) TCR bound to HLA-DQ2.5-glia-alpha1a and HLA-DQ2.5-glia-omega1, as well as the structure of an epitope-specific TRAV9-2(+)-TRBV7-3(+) TCR-HLA-DQ2.5-glia-omega1 complex. We found that position 7 (p7) of the DQ2.5-glia-alpha1a and DQ2.5-glia-omega1 epitopes made very limited contacts with the TRAV4(+) TCR, thereby explaining the TCR cross-reactivity across these two epitopes. In contrast, within the TRAV9-2(+) TCR-HLA-DQ2.5-glia-omega1 ternary complex, the p7-Gln was situated in an electrostatic pocket formed by the hypervariable CDR3beta loop of the TCR and Arg70beta from HLA-DQ2.5, a polar network which would not be supported by the p7-Leu residue of DQ2.5-glia-alpha1a. In conclusion, we provide additional insights into the molecular determinants of TCR specificity and cross-reactivity to two closely-related epitopes in celiac disease.

Structural basis of T cell receptor specificity and cross-reactivity of two HLA-DQ2.5-restricted gluten epitopes in celiac disease.,Ciacchi L, Farenc C, Dahal-Koirala S, Petersen J, Sollid LM, Reid HH, Rossjohn J J Biol Chem. 2022 Mar;298(3):101619. doi: 10.1016/j.jbc.2022.101619. Epub 2022 , Jan 21. PMID:35065967<ref>PMID:35065967</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7sg2" style="background-color:#fffaf0;"></div>

==See Also==
*[[MHC 3D structures|MHC 3D structures]]
*[[MHC II 3D structures|MHC II 3D structures]]
*[[T-cell receptor 3D structures|T-cell receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ciacchi L]]
[[Category: Farenc C]]
[[Category: Petersen J]]
[[Category: Reid HH]]
[[Category: Rossjohn J]]