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A new twist in TCR diversity revealed by a forbidden alphabeta TCR |
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| Authors: | McBeth Christine Seamons Audrey Pizarro Juan C Fleishman Sarel J Baker David Kortemme Tanja Goverman Joan M Strong Roland K |
| Affiliation: | 1 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA 2 Department of Immunology, University of Washington, Seattle, WA 98195, USA 3 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA 4 Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143, USA 5 Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA |
| Abstract: | We report crystal structures of a negatively selected T cell receptor (TCR) that recognizes two I-Au-restricted myelin basic protein peptides and one of its peptide/major histocompatibility complex (pMHC) ligands. Unusual complementarity-determining region (CDR) structural features revealed by our analyses identify a previously unrecognized mechanism by which the highly variable CDR3 regions define ligand specificity. In addition to the pMHC contact residues contributed by CDR3, the CDR3 residues buried deep within the Vα/Vβ interface exert indirect effects on recognition by influencing the Vα/Vβ interdomain angle. This phenomenon represents an additional mechanism for increasing the potential diversity of the TCR repertoire. Both the direct and indirect effects exerted by CDR residues can impact global TCR/MHC docking. Analysis of the available TCR structures in light of these results highlights the significance of the Vα/Vβ interdomain angle in determining specificity and indicates that TCR/pMHC interface features do not distinguish autoimmune from non-autoimmune class II-restricted TCRs. |
| Keywords: | CDR, complementarity-determining region TCR, T cell receptor scTCR, single chain format TCR pMHC, peptide/ major histocompatibility complex EAE, experimental autoimmune encephalomyelitis MBP, myelin basic protein NCS, non-crystallographic symmetry AU, asymmetric unit RMSD, root-mean-square deviation SEC, size-exclusion chromatography |
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