7SG1

XPA5 TCR in complex with HLA-DQ2-alpha1

Summary for 7SG1

• Entry DOI: 10.2210/pdb7sg1/pdb
• Descriptor: HLA class II histocompatibility antigen, DQ alpha 1 chain, MHC class II HLA-DQ-beta-1, T-cell receptor, xpa5, alpha chain, ... (8 entities in total)
• Functional Keywords: tcr-pmhc, celiac disease, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 10
• Total formula weight: 194951.61

Authors

Ciacchi, L.,Farenc, C.,Petersen, J.,Reid, H.H.,Rossjohn, J. (deposition date: 2021-10-04, release date: 2022-02-23, Last modification date: 2024-10-23)

Primary citation

Ciacchi, L.,Farenc, C.,Dahal-Koirala, S.,Petersen, J.,Sollid, L.M.,Reid, H.H.,Rossjohn, J.
Structural basis of T cell receptor specificity and cross-reactivity of two HLA-DQ2.5-restricted gluten epitopes in celiac disease.
J.Biol.Chem., 298:101619-101619, 2022

PubMed Abstract: 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-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (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-α1a and HLA-DQ2.5-glia-ω1 with similar affinity, whereas a TRAV4 (TRAV9-2) TCR recognized HLA-DQ2.5-glia-ω1 only. We further determined the crystal structures of the TRAV4-TRBV29-1 TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1, as well as the structure of an epitope-specific TRAV9-2-TRBV7-3 TCR-HLA-DQ2.5-glia-ω1 complex. We found that position 7 (p7) of the DQ2.5-glia-α1a and DQ2.5-glia-ω1 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-ω1 ternary complex, the p7-Gln was situated in an electrostatic pocket formed by the hypervariable CDR3β loop of the TCR and Arg70β from HLA-DQ2.5, a polar network which would not be supported by the p7-Leu residue of DQ2.5-glia-α1a. In conclusion, we provide additional insights into the molecular determinants of TCR specificity and cross-reactivity to two closely-related epitopes in celiac disease.

PubMed: 35065967
DOI: 10.1016/j.jbc.2022.101619

Experimental method

X-RAY DIFFRACTION (3.1 Å)