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Structural Features of the ??TCR Mechanotransduction Apparatus That Promote pMHC Discrimination.

ABSTRACT: 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 C?FG 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.

SUBMITTER: Brazin KN

PROVIDER: S-EPMC4558533 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination.

Brazin Kristine N KN Mallis Robert J RJ Das Dibyendu Kumar DK Feng Yinnian Y Hwang Wonmuk W Wang Jia-Huai JH Wagner Gerhard G Lang Matthew J MJ Reinherz Ellis L EL

Frontiers in immunology 20150903

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 allostericall ...[more]

PMID: 26388869

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Project description:Key pointsTrabecular meshwork (TM) is a highly mechanosensitive tissue in the eye that regulates intraocular pressure through the control of aqueous humour drainage. Its dysfunction underlies the progression of glaucoma but neither the mechanisms through which TM cells sense pressure nor their role in aqueous humour outflow are understood at the molecular level. We identified the Piezo1 channel as a key TM transducer of tensile stretch, shear flow and pressure. Its activation resulted in intracellular signals that altered organization of the cytoskeleton and cell-extracellular matrix contacts and modulated the trabecular component of aqueous outflow whereas another channel, TRPV4, mediated a delayed mechanoresponse. This study helps elucidate basic mechanotransduction properties that may contribute to intraocular pressure regulation in the vertebrate eye.AbstractChronic elevations in intraocular pressure (IOP) can cause blindness by compromising the function of trabecular meshwork (TM) cells in the anterior eye, but how these cells sense and transduce pressure stimuli is poorly understood. Here, we demonstrate functional expression of two mechanically activated channels in human TM cells. Pressure-induced cell stretch evoked a rapid increase in transmembrane current that was inhibited by antagonists of the mechanogated channel Piezo1, Ruthenium Red and GsMTx4, and attenuated in Piezo1-deficient cells. The majority of TM cells exhibited a delayed stretch-activated current that was mediated independently of Piezo1 by TRPV4 (transient receptor potential cation channel, subfamily V, member 4) channels. Piezo1 functions as the principal TM transducer of physiological levels of shear stress, with both shear and the Piezo1 agonist Yoda1 increasing the number of focal cell-matrix contacts. Analysis of TM-dependent fluid drainage from the anterior eye showed significant inhibition by GsMTx4. Collectively, these results suggest that TM mechanosensitivity utilizes kinetically, regulatory and functionally distinct pressure transducers to inform the cells about force-sensing contexts. Piezo1-dependent control of shear flow sensing, calcium homeostasis, cytoskeletal dynamics and pressure-dependent outflow suggests potential for a novel therapeutic target in treating glaucoma.

Dataset Information

Structural Features of the ??TCR Mechanotransduction Apparatus That Promote pMHC Discrimination.

Publications

Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination.

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