Thermoring basis for thermo-gated TRPV2

Thermodynamic coupling between cold and heat activations of TRPV2 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Thermodynamic coupling between cold and heat activations of TRPV2 Guangyu Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6049325/v3 This work is licensed under a CC BY 4.0 License Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Abstract The homotetrameric thermosensitive transient receptor potential vanilloid 2 (TRPV2) channel is a biological macromolecule with unique high temperature threshold and sensitivity. However, the underlying thermodynamic basis has not been well understood. In this computational study, the 3D cryo-EM structures of rat TRPV2 in response to various chemical perturbations at different sites at low temperatures were quantified at the tertiary and quaternary levels using a highly sensitive thermoring model. The results indicated that a putative stable pre-open closed state without a lipid at the well-known active vanilloid site exhibited at least three weakest tertiary noncovalent bridges on the protein surface as primary thermal sensors with matched thresholds for initial heat activation. Any chemical perturbation away from these sensors activated the channel but with lower cold sensitivity. In contrast, when the sensors were simultaneously exposed to a mild detergent, together with hydrolysis of nearby charged residues at the membrane surface, the channel could be opened with the unique high cold sensitivity similarly to mirror the initial heat sensation. Further, disrupting intersubunit interactions near the heat sensors was required for full channel opening at both upper and lower gates. Therefore, the heat capacity mechanism, once cross-examined, could be applied to elucidate the unique thermoring basis for the sharp heat response of thermosensitive TRPV2 above body temperature. (213 words) Biophysics Computational Biology Structural Biology Bioinformatics Systems Biology Chemical Biology Mathematical and Theoretical Biology Physiology Computational Neuroscience Computational Chemistry Biological Chemistry Topology ion channel gating mirrored thermosensitivity noncovalent thermoring structure protein-lipid interaction threshold unfolding dynamics Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementarymaterialthermoswitchesinTRPV2R2.0clear.pdf Cite Share Download PDF Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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However, the underlying thermodynamic basis has not been well understood. In this computational study, the 3D cryo-EM structures of rat TRPV2 in response to various chemical perturbations at different sites at low temperatures were quantified at the tertiary and quaternary levels using a highly sensitive thermoring model. The results indicated that a putative stable pre-open closed state without a lipid at the well-known active vanilloid site exhibited at least three weakest tertiary noncovalent bridges on the protein surface as primary thermal sensors with matched thresholds for initial heat activation. Any chemical perturbation away from these sensors activated the channel but with lower cold sensitivity. In contrast, when the sensors were simultaneously exposed to a mild detergent, together with hydrolysis of nearby charged residues at the membrane surface, the channel could be opened with the unique high cold sensitivity similarly to mirror the initial heat sensation. 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