T Cell Receptor Recognition via Cooperative Conformational Plasticity

• Published in: Journal of molecular biology 2006-10, Vol.363 (1), p.228-243
• Main Authors: Gagnon, Susan J., Borbulevych, Oleg Y., Davis-Harrison, Rebecca L., Turner, Richard V., Damirjian, Marale, Wojnarowicz, Alison, Biddison, William E., Baker, Brian M.
• Format: Article
• Language: English
• Subjects: binding; Cross-Priming - immunology; cross-reactivity; crystallography; Crystallography, X-Ray; Gene Products, tax - chemistry; Gene Products, tax - metabolism; HLA-A2 Antigen - chemistry; HLA-A2 Antigen - metabolism; Human T-lymphotropic virus 1; Humans; MHC; Protein Binding; Protein Conformation; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - metabolism; T cell receptor
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2006.08.045

Although T cell receptor cross-reactivity is a fundamental property of the immune system and is implicated in numerous autoimmune pathologies, the molecular mechanisms by which T cell receptors can recognize and respond to diverse ligands are incompletely understood. In the current study we examined the response of the human T cell lymphotropic virus-1 (HTLV-1) Tax-specific T cell receptor (TCR) A6 to a panel of structurally distinct haptens coupled to the Tax 11-19 peptide with a lysine substitution at position 5 (Tax5K, LLFG[K-hapten]PVYV). The A6 TCR could cross-reactively recognize one of these haptenated peptides, Tax-5K-4-(3-Indolyl)-butyric acid (IBA), presented by HLA-A*0201. The crystal structures of Tax5K-IBA/HLA-A2 free and in complex with A6 reveal that binding is mediated by a mechanism of cooperative conformational plasticity involving conformational changes on both sides of the protein–protein interface, including the TCR complementarity determining region (CDR) loops, Vα/Vβ domain orientation, and the hapten-modified peptide. Our findings illustrate the complex role that protein dynamics can play in TCR cross-reactivity and highlight that T cell receptor recognition of ligand can be achieved through diverse and complex molecular mechanisms that can occur simultaneously in the interface, not limited to molecular mimicry and CDR loop shifts.