title: Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination.
abstract: The αβTCR 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 CβFG loop region positioned between Vβ and Cβ domains that allosterically gates both dynamic T cell receptor (TCR)-pMHC bond formation and lifetime; (2) the rigid super β-sheet amalgams of heterodimeric CD3εγ and CD3εδ ectodomain components of the αβTCR complex; (3) the αβTCR 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 αβTCR complex that accompany pMHC ligation under load. How bioforces foster specific αβTCR-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 αβTCR 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 αβTCR to interact with self-pMHC ligands, impacting early thymic repertoire selection prior to the CD4(+)CD8(+) double positive thymocyte stage of development.
authors.affiliation: Laboratory of Immunobiology, Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA , USA ; Department of Medicine, Harvard Medical School , Boston, MA , USA.
authors.forename: Kristine N
authors.initials: KN
authors.lastname: Brazin
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, MA , USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mallis
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University , Nashville, TN , USA.
authors.forename: Dibyendu Kumar
authors.initials: DK
authors.lastname: Das
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University , Nashville, TN , USA.
authors.forename: Yinnian
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Biomedical Engineering, Texas A&M University , College Station, TX , USA ; Department of Materials Science and Engineering, Texas A&M University , College Station, TX , USA ; School of Computational Sciences, Korea Institute for Advanced Study , Seoul , South Korea.
authors.forename: Wonmuk
authors.initials: W
authors.lastname: Hwang
authors.affiliation: Laboratory of Immunobiology, Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA , USA ; Department of Medicine, Harvard Medical School , Boston, MA , USA ; Department of Pediatrics, Harvard Medical School , Boston, MA , USA.
authors.forename: Jia-Huai
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, MA , USA.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University , Nashville, TN , USA ; Department of Molecular Physiology and Biophysics, Vanderbilt University , Nashville, TN , USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lang
authors.affiliation: Laboratory of Immunobiology, Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA , USA ; Department of Medicine, Harvard Medical School , Boston, MA , USA.
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
keywords: CD3; T cell receptor; antigen recognition; catch bond; kinetic proofreading; mechanosensor; pre-TCR; thymic development