A study of CDR3 loop dynamics reveals distinct mechanisms of peptide recognition by T-cell receptors exhibiting different levels of cross-reactivity

Yuko Tsuchiya, Yoshiki Namiuchi, Hiroshi Wako, Hiromichi Tsurui

研究成果: Article

2 引用 (Scopus)

抄録

T-cell receptors (TCRs) can productively interact with many different peptides bound within the MHC binding groove. This property varies with the level of cross-reactivity of TCRs; some TCRs are particularly hyper cross-reactive while others exhibit greater specificity. To elucidate the mechanism behind these differences, we studied five TCRs in complex with the same class II MHC (1Ab)-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 TCRs in a free state, as well as the relationship between binding affinity and interface area. It was found that the TCRs 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, TCRs 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 CDR3β dominated. As entropy loss upon binding in these highly degenerate and rigid TCRs is smaller than that in less degenerate TCRs, 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 TCRs appear to correlate with the levels of T-cell cross-reactivity.

元の言語English
ページ(範囲)466-478
ページ数13
ジャーナルImmunology
153
発行部数4
DOI
出版物ステータスPublished - 2018 4 1

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Peptide T
T-Cell Antigen Receptor
Peptides
Entropy
Hydrogen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

これを引用

A study of CDR3 loop dynamics reveals distinct mechanisms of peptide recognition by T-cell receptors exhibiting different levels of cross-reactivity. / Tsuchiya, Yuko; Namiuchi, Yoshiki; Wako, Hiroshi; Tsurui, Hiromichi.

:: Immunology, 巻 153, 番号 4, 01.04.2018, p. 466-478.

研究成果: Article

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AB - T-cell receptors (TCRs) can productively interact with many different peptides bound within the MHC binding groove. This property varies with the level of cross-reactivity of TCRs; some TCRs are particularly hyper cross-reactive while others exhibit greater specificity. To elucidate the mechanism behind these differences, we studied five TCRs in complex with the same class II MHC (1Ab)-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 TCRs in a free state, as well as the relationship between binding affinity and interface area. It was found that the TCRs 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, TCRs 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 CDR3β dominated. As entropy loss upon binding in these highly degenerate and rigid TCRs is smaller than that in less degenerate TCRs, 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 TCRs appear to correlate with the levels of T-cell cross-reactivity.

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