Probing the Conformational Dynamics of Affinity-Enhanced T Cell Receptor Variants upon Binding the Peptide-Bound Major Histocompatibility Complex by Hydrogen/Deuterium Exchange Mass Spectrometry.

Détails

ID Serval
serval:BIB_CF7649E47A67
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Probing the Conformational Dynamics of Affinity-Enhanced T Cell Receptor Variants upon Binding the Peptide-Bound Major Histocompatibility Complex by Hydrogen/Deuterium Exchange Mass Spectrometry.
Périodique
Biochemistry
Auteur(s)
Merkle P.S., Trabjerg E., Hongjian S., Ferber M., Cuendet M.A., Jørgensen TJD, Luescher I., Irving M., Zoete V., Michielin O., Rand K.D.
ISSN
1520-4995 (Electronic)
ISSN-L
0006-2960
Statut éditorial
Publié
Date de publication
23/03/2021
Peer-reviewed
Oui
Volume
60
Numéro
11
Pages
859-872
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Binding of the T cell receptor (TCR) to its cognate, peptide antigen-loaded major histocompatibility complex (pMHC) is a key interaction for triggering T cell activation and ultimately elimination of the target cell. Despite the importance of this interaction for cellular immunity, a comprehensive molecular understanding of TCR specificity and affinity is lacking. We conducted hydrogen/deuterium exchange mass spectrometry (HDX-MS) analyses of individual affinity-enhanced TCR variants and clinically relevant pMHC class I molecules (HLA-A*0201/NY-ESO-1 <sub>157-165</sub> ) to investigate the causality between increased binding affinity and conformational dynamics in TCR-pMHC complexes. Differential HDX-MS analyses of TCR variants revealed that mutations for affinity enhancement in TCR CDRs altered the conformational response of TCR to pMHC ligation. Improved pMHC binding affinity was in general observed to correlate with greater differences in HDX upon pMHC binding in modified TCR CDR loops, thereby providing new insights into the TCR-pMHC interaction. Furthermore, a specific point mutation in the β-CDR3 loop of the NY-ESO-1 TCR associated with a substantial increase in binding affinity resulted in a substantial change in pMHC binding kinetics (i.e., very slow k <sub>on</sub> , revealed by the detection of EX1 HDX kinetics), thus providing experimental evidence for a slow induced-fit binding mode. We also examined the conformational impact of pMHC binding on an unrelated TRAV12-2 gene-encoded TCR directed against the immunodominant MART-1 <sub>26-35</sub> cancer antigen restricted by HLA-A*0201. Our findings provide a molecular basis for the observed TRAV12-2 gene bias in natural CD8 <sup>+</sup> T cell-based immune responses against the MART-1 antigen, with potential implications for general ligand discrimination and TCR cross-reactivity processes.
Pubmed
Web of science
Création de la notice
15/03/2021 14:41
Dernière modification de la notice
22/09/2021 6:38
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