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T-cell Receptor (TCR)-Peptide Specificity Overrides Affinity-enhancing TCR-Major Histocompatibility Complex Interactions

DOI: 10.1074/jbc.M113.522110 DOI Help
PMID: 24196962 PMID Help

Authors: David K. Cole (Cardiff University School of Medicine) , Kim Miles (Cardiff University) , Florian Madura (Cardiff University) , Chris Holland (Cardiff University) , Andrea Schauenburg (Cardiff University) , Andrew J. Godkin (Cardiff University) , Anna Bulek (Cardiff University) , Anna Fuller (Cardiff University) , Hephzibah Akpovwa (Cardiff University) , Philip G Pymm (Cardiff University) , Nathaniel Liddy (Immunocore Ltd) , Malkit Sami (Immunocore Ltd) , Yi Li (Immunocore Ltd) , Pierre Rizkallah (Cardiff University) , Bent K. Jakobsen (Immunocore Ltd) , Andrew K. Sewell (Cardiff University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 289 (2) , PAGES 628 - 638

State: Published (Approved)
Published: January 2014

Open Access Open Access

Abstract: This work was supported by the Medical Research Council (to A. K. S., T. J. G., and I. B.), Central Laboratory of the Research Councils (CLRC) Daresbury Laboratory, the Diamond Light Source (Midlands BAG MX310), the Danish Medical Research Council (to U. H.), the NOVO Nordic Foundation (to U. H.αβ T-cell receptors (TCRs) engage antigens using complementarity-determining region (CDR) loops that are either germ line-encoded (CDR1 and CDR2) or somatically rearranged (CDR3). TCR ligands compose a presentation platform (major histocompatibility complex (MHC)) and a variable antigenic component consisting of a short “foreign” peptide. The sequence of events when the TCR engages its peptide-MHC (pMHC) ligand remains unclear. Some studies suggest that the germ line elements of the TCR engage the MHC prior to peptide scanning, but this order of binding is difficult to reconcile with some TCR-pMHC structures. Here, we used TCRs that exhibited enhanced pMHC binding as a result of mutations in either CDR2 and/or CDR3 loops, that bound to the MHC or peptide, respectively, to dissect the roles of these loops in stabilizing TCR-pMHC interactions. Our data show that TCR-peptide interactions play a strongly dominant energetic role providing a binding mode that is both temporally and energetically complementary with a system requiring positive selection by self-pMHC in the thymus and rapid recognition of non-self-pMHC in the periphery. ), the Lundbeck Foundation (U. H.), and Fonden til Lægevidenskabens Fremme (to U. H.).

Journal Keywords: Binding; Competitive; Complementarity; Crystallography; X-Ray; HLA; HLA-A2; Humans; Kinetics; Ligands; Models; Molecular; Mutation; Oligopeptides; Peptides; Protein; Tertiary; Receptors; Antigen; T-Cell; T-Cell Antigen Receptor Specificity

Subject Areas: Medicine, Biology and Bio-materials, Chemistry

Instruments: I04-Macromolecular Crystallography