Conformational changes and flexibility in T-cell receptor recognition of peptide - MHC complexes

Kathryn M. Armstrong, Kurt H. Piepenbrink, Brian M. Baker

Research output: Contribution to journalReview article

78 Scopus citations

Abstract

A necessary feature of the immune system, TCR (T-cell receptor) cross-reactivity has been implicated in numerous autoimmune pathologies and is an underlying cause of transplant rejection. Early studies of the interactions of αβ TCRs (T-cell receptors) with their peptide-MHC ligands suggested that conformational plasticity in the TCR CDR (complementarity determining region) loops is a dominant contributor to T-cell cross-reactivity. Since these initial studies, the database of TCRs whose structures have been solved both bound and free is now large enough to permit general conclusions to be drawn about the extent of TCR plasticity and the types and locations of motion that occur. In the present paper, we review the conformational differences between free and bound TCRs, quantifying the structural changes that occur and discussing their possible roles in specificity and cross-reactivity. We show that, rather than undergoing major structural alterations or 'folding' upon binding, the majority of TCR CDR loops shift by relatively small amounts. The structural changes that do occur are dominated by hinge-bending motions, with loop remodelling usually occurring near loop apexes. As predicted from previous studies, the largest changes are in the hypervariable CDR3α and CDR3β loops, although in some cases the germline-encoded CDR1α and CDR2α loops shift in magnitudes that approximate those of the CDR3 loops. Intriguingly, the smallest shifts are in the germline-encoded loops of the β-chain, consistent with recent suggestions that the TCR β domain may drive ligand recognition.

Original languageEnglish (US)
Pages (from-to)183-196
Number of pages14
JournalBiochemical Journal
Volume415
Issue number2
DOIs
Publication statusPublished - Oct 15 2008

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Keywords

  • Conformational selection
  • Cross-reactivity
  • Crystal structure
  • Induced fit
  • Peptide-MHC (pMHC)
  • T-cell receptor (TCR)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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