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Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • T-CELL-RECEPTOR
  • FORCE
  • ACTIVATION
  • KINETICS
  • BINDING
  • SEGREGATION
  • DYNAMICS
  • COMPLEX
  • SYNAPSE
  • MODEL

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

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Journal Title:

MOLECULAR CELL

Volume:

Volume 73, Number 5

Publisher:

, Pages 1015-+

Type of Work:

Article

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.
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