Asymmetric framework motion of TCRαβ controls load-dependent peptide discrimination
- Texas A&M University, United States
- Dana-Farber Cancer Institute, United States
- Vanderbilt University, United States
Abstract
Mechanical force is critical for the interaction between an αβT cell receptor (TCR) and a peptide-bound major histocompatibility complex (pMHC) molecule to initiate productive T-cell activation. However, the underlying mechanism remains unclear. We use all-atom molecular dynamics simulations to examine the A6 TCR bound to HLA-A*02:01 presenting agonist or antagonist peptides under different extensions to simulate the effects of applied load on the complex, elucidating their divergent biological responses. We found that TCR α and β chains move asymmetrically, which impacts the interface with pMHC, in particular the peptide-sensing CDR3 loops. For the wild-type agonist, the complex stabilizes in a load-dependent manner while antagonists destabilize it. Simulations of the Cβ FG-loop deletion, which reduces the catch bond response, and simulations with in silico mutant peptides further support the observed behaviors. The present results highlight the combined role of interdomain motion, fluctuating forces, and interfacial contacts in determining the mechanical response and fine peptide discrimination by a TCR, thereby resolving the conundrum of nearly identical crystal structures of TCRαβ-pMHC agonist and antagonist complexes.
Data availability
The current manuscript is a computational study, so no data have been generated for this manuscript. Sample analysis scripts are available on GitHub: https://github.com/hwm2746/a6tcr_anal_md/tree/main
Article and author information
Author details
Ana Cristina Chang-Gonzalez
Funding
US National Institutes of Health (P01AI143565)
- Robert J Mallis
- Matthew J Lang
- Ellis L Reinherz
- Wonmuk Hwang
US National Institutes of Health (R01AI136301)
- Matthew J Lang
- Ellis L Reinherz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2024, Chang-Gonzalez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Asymmetric framework motion of TCRαβ controls load-dependent peptide discrimination
eLife 13:e91881.
https://doi.org/10.7554/eLife.91881
