Structural Features of the TCR Mechanotransduction Apparatus That Promote pMHC Discrimination.
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The TCR was recently revealed to function as a mechanoreceptor. That is, it leverages mechanical energy generated during immune surveillance and at the immunological synapse to drive biochemical signaling following ligation by a specific foreign peptide-MHC complex (pMHC). Here, we review the structural features that optimize this transmembrane (TM) receptor for mechanotransduction. Specialized adaptations include (1) the CFG loop region positioned between V and C domains that allosterically gates both dynamic T cell receptor (TCR)-pMHC bond formation and lifetime; (2) the rigid super -sheet amalgams of heterodimeric CD3 and CD3 ectodomain components of the TCR complex; (3) the TCR subunit connecting peptides linking the extracellular and TM segments, particularly the oxidized CxxC motif in each CD3 heterodimeric subunit that facilitates force transfer through the TM segments and surrounding lipid, impacting cytoplasmic tail conformation; and (4) quaternary changes in the TCR complex that accompany pMHC ligation under load. How bioforces foster specific TCR-based pMHC discrimination and why dynamic bond formation is a primary basis for kinetic proofreading are discussed. We suggest that the details of the molecular rearrangements of individual TCR subunit components can be analyzed utilizing a combination of structural biology, single-molecule FRET, optical tweezers, and nanobiology, guided by insightful atomistic molecular dynamic studies. Finally, we review very recent data showing that the pre-TCR complex employs a similar mechanobiology to that of the TCR to interact with self-pMHC ligands, impacting early thymic repertoire selection prior to the CD4(+)CD8(+) double positive thymocyte stage of development.