Catch bond models may explain how force amplifies TCR signaling and antigen discrimination

• Type of Material: Article
• Authors: Hyun-Kyu Choi, Georgia Institute of Technology; Peiwen Cong, Georgia Institute of Technology; Chenghao Ge, Georgia Institute of Technology; Aswin Natarajan, New York University Grossman School of Medicine; Baoyu Liu, Georgia Institute of Technology; Yong Zhang, Chinese Academy of Sciences; Kaitao Li, Georgia Institute of Technology; Muaz Nik Rushdi, Georgia Institute of Technology; Wei Chen, Zhejiang University; Jizhong Lou, Chinese Academy of Sciences; Michelle Krogsgaard, New York University Grossman School of Medicine; Cheng Zhu, Emory University
• Language: English
• Date: 2023-05-05
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-38267-1
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 14
• Issue: 1
• Start Page: 2616
• End Page: 2616
• Keywords: CHAIN; T-CELL-RECEPTOR; Science & Technology - Other Topics; Multidisciplinary Sciences; LIGAND BINDING-KINETICS; RECOGNITION; DISSOCIATION; TRANSITION; STRUCTURAL BASIS; MOLECULES; DIFFUSION-MODEL; ADHESION; Science & Technology
• Research Categories: Engineering, Mechanical; Health Sciences, Pathology; Engineering, Biomedical

Abstract

The TCR integrates forces in its triggering process upon interaction with pMHC. Force elicits TCR catch-slip bonds with strong pMHCs but slip-only bonds with weak pMHCs. We develop two models and apply them to analyze 55 datasets, demonstrating the models’ ability to quantitatively integrate and classify a broad range of bond behaviors and biological activities. Comparing to a generic two-state model, our models can distinguish class I from class II MHCs and correlate their structural parameters with the TCR/pMHC’s potency to trigger T cell activation. The models are tested by mutagenesis using an MHC and a TCR mutated to alter conformation changes. The extensive comparisons between theory and experiment provide model validation and testable hypothesis regarding specific conformational changes that control bond profiles, thereby suggesting structural mechanisms for the inner workings of the TCR mechanosensing machinery and plausible explanations of why and how force may amplify TCR signaling and antigen discrimination.