Premium
A study of CDR 3 loop dynamics reveals distinct mechanisms of peptide recognition by T‐cell receptors exhibiting different levels of cross‐reactivity
Author(s) -
Tsuchiya Yuko,
Namiuchi Yoshiki,
Wako Hiroshi,
Tsurui Hiromichi
Publication year - 2018
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12849
Subject(s) - receptor , reactivity (psychology) , peptide , biology , dynamics (music) , computational biology , microbiology and biotechnology , genetics , biochemistry , physics , medicine , alternative medicine , pathology , acoustics
Summary T‐cell receptors ( TCR s) can productively interact with many different peptides bound within the MHC binding groove. This property varies with the level of cross‐reactivity of TCR s; some TCR s are particularly hyper cross‐reactive while others exhibit greater specificity. To elucidate the mechanism behind these differences, we studied five TCR s in complex with the same class II MHC (1A b )‐peptide (3K), that are known to exhibit different levels of cross‐reactivity. Although these complexes have similar binding affinities, the interface areas between the TCR and the peptide– MHC ( pMHC ) differ significantly. We investigated static and dynamic structural features of the TCR – pMHC complexes and of TCR s in a free state, as well as the relationship between binding affinity and interface area. It was found that the TCR s known to exhibit lower levels of cross‐reactivity bound to pMHC using an induced‐fitting mechanism, forming large and tight interfaces rich in specific hydrogen bonds. In contrast, TCR s known to exhibit high levels of cross‐reactivity used a more rigid binding mechanism where non‐specific π ‐interactions involving the bulky Trp residue in CDR 3 β dominated. As entropy loss upon binding in these highly degenerate and rigid TCR s is smaller than that in less degenerate TCR s, they can better tolerate changes in residues distal from the major contacts with MHC ‐bound peptide. Hence, our dynamics study revealed that differences in the peptide recognition mechanisms by TCR s appear to correlate with the levels of T‐cell cross‐reactivity.