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Reinherz Ellis L.; Mallis, Robert J.; Kumar Das, Dibyendu; Feng, Yinnian; Hwang, Wonmuk; Wang, Jia-huai; Wagner, Gerhard; Lang, Matthew J.; Brazin, Kristine N.
JAIDS Journal of Acquired Immune Deficiency Syndromes: January 2016
doi: 10.1097/01.qai.0000479564.74979.ea
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The abTCR 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). I shall review the specialized structural adaptations that optimize this transmembrane receptor for mechanotransduction including (1) the CbFG loop region positioned between Vb and Cb domains that allosterically gates both dynamic TCR-pMHC bond formation and lifetime; (2) the rigid super b-sheet amalgams of heterodimeric CD3eg as well as CD3ed ectodomain components of the αβTCR complex; (3) the abTCR subunit connecting peptides (CP) linking the extracellular and transmembrane (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 abTCR complex that accompany pMHC ligation under load. How bioforces foster specific abTCR-based pMHC discrimination and why dynamic bond formation is a primary basis for kinetic proofreading are discussed with emphasis on pathogen and tumor recognition. Finally, I will review data showing that the preTCR complex employs a similar mechanobiology to that of the abTCR to interact with self-pMHC ligands, impacting early thymic repertoire selection prior to the CD4+CD8+ double positive thymocyte stage of development.

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