Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition

• Type of Material: Article
• Authors: Peng Wu, Zhejiang University; Tongtong Zhang, Zhejiang University; Baoyu Liu, Georgia Institute of Technology; Panyu Fei, Zhejiang University; Lei Cui, Chinese Academy of Sciences; Rui Qin, Zhejiang University; Huaying Zhu, Zhejiang University; Danmei Yao, Zhejiang University; Ryan J. Martinez, Emory University; Wei Hu, Zhejiang University; Chenyi An, Zhejiang University; Yong Zhang, Chinese Academy of Sciences; Junwei Liu, Zhejiang University; Jiawei Shi, Zhejiang University; Juan Fan, Zhejiang University; Weiwei Yin, Zhejiang University; Jie Sun, Zhejiang University; Chun Zhou, Zhejiang University; Xun Zeng, Zhejiang University; Chenqi Xu, Chinese Academy of Sciences; Jianan Wang, Zhejiang University; Brian Evavold, Emory University; Cheng Zhu, Emory University; Wei Chen, Zhejiang University; Jizhong Lou, Chinese Academy of Sciences
• Language: English
• Date: 2019-03-07
• Publisher: Cell Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2018.12.018
• Title of Journal or Parent Work: Molecular Cell
• Volume: 73
• Issue: 5
• Start Page: 1015
• End Page: +
• Grant/Funding Information: This work was supported by grants from the National Basic Research Program of China (2015CB910800 to W.C. and 2014CB910202 to J.L.), the National Science Foundation of China (31470900 and 31522021 to W.C.; 11672317 and 31222022 to J.L.), the Fundamental Research Funds for the Central Universities (2015XZZX004-32 to W.C.), the National Institutes of Health of America (U01CA214354 and R01AI124680 to C. Zhu. and R01AI096879 to B.E.).; The computational resources were provided by the National Supercomputing Center Tianjin Center and HPC-Service Station at the Center for Biological Imaging of the Institute of Biophysics.
• Keywords: Binding; Dynamics; Kinetics; Model; Cell Biology; Force; Synapse; Activation; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; T-cell receptor; Segregation; Complex; Science & Technology
• Research Categories: Biology, Neuroscience; Biology, Microbiology; Biology, Cell; Health Sciences, Immunology

Abstract

TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy. Wu et al. report that a dynamic structural mechanism of mechano-chemical coupling for TCR antigen recognition—that is, mechanical force-induced conformational changes in the agonist peptide-MHC-I—allosterically activates TCR-pMHC-I catch bonds to determine TCR antigen recognition and trigger T cell signaling.