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Temperature sensitive contact modes allosterically gate TRPV3

TRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-EM structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TR...

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Autores principales: Burns, Daniel, Venditti, Vincenzo, Potoyan, Davit A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599574/
https://www.ncbi.nlm.nih.gov/pubmed/37831724
http://dx.doi.org/10.1371/journal.pcbi.1011545
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author Burns, Daniel
Venditti, Vincenzo
Potoyan, Davit A.
author_facet Burns, Daniel
Venditti, Vincenzo
Potoyan, Davit A.
author_sort Burns, Daniel
collection PubMed
description TRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-EM structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TRPV channels establish precise and robust temperature sensing remain elusive. In this work we employ molecular simulations, multi-ensemble contact analysis, graph theory, and machine learning techniques to reveal the temperature-sensitive residue-residue interactions driving allostery in TRPV3. We find that groups of residues exhibiting similar temperature-dependent contact frequency profiles cluster at specific regions of the channel. The dominant mode clusters on the ankyrin repeat domain and displays a linear melting trend while others display non-linear trends. These modes describe the residue-level temperature response patterns that underlie the channel’s functional dynamics. With network analysis, we find that the community structure of the channel changes with temperature. And that a network of high centrality contacts connects distant regions of the protomer to the gate, serving as a means for the temperature-sensitive contact modes to allosterically regulate channel gating. Using a random forest model, we show that the contact states of specific temperature-sensitive modes are indeed predictive of the channel gate’s state. Supporting the physical validity of these modes and networks are several residues identified with our analyses that are reported in literature to be functionally critical. Our results offer high resolution insight into thermo-TRP channel function and demonstrate the utility of temperature-sensitive contact analysis.
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spelling pubmed-105995742023-10-26 Temperature sensitive contact modes allosterically gate TRPV3 Burns, Daniel Venditti, Vincenzo Potoyan, Davit A. PLoS Comput Biol Research Article TRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-EM structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TRPV channels establish precise and robust temperature sensing remain elusive. In this work we employ molecular simulations, multi-ensemble contact analysis, graph theory, and machine learning techniques to reveal the temperature-sensitive residue-residue interactions driving allostery in TRPV3. We find that groups of residues exhibiting similar temperature-dependent contact frequency profiles cluster at specific regions of the channel. The dominant mode clusters on the ankyrin repeat domain and displays a linear melting trend while others display non-linear trends. These modes describe the residue-level temperature response patterns that underlie the channel’s functional dynamics. With network analysis, we find that the community structure of the channel changes with temperature. And that a network of high centrality contacts connects distant regions of the protomer to the gate, serving as a means for the temperature-sensitive contact modes to allosterically regulate channel gating. Using a random forest model, we show that the contact states of specific temperature-sensitive modes are indeed predictive of the channel gate’s state. Supporting the physical validity of these modes and networks are several residues identified with our analyses that are reported in literature to be functionally critical. Our results offer high resolution insight into thermo-TRP channel function and demonstrate the utility of temperature-sensitive contact analysis. Public Library of Science 2023-10-13 /pmc/articles/PMC10599574/ /pubmed/37831724 http://dx.doi.org/10.1371/journal.pcbi.1011545 Text en © 2023 Burns et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Burns, Daniel
Venditti, Vincenzo
Potoyan, Davit A.
Temperature sensitive contact modes allosterically gate TRPV3
title Temperature sensitive contact modes allosterically gate TRPV3
title_full Temperature sensitive contact modes allosterically gate TRPV3
title_fullStr Temperature sensitive contact modes allosterically gate TRPV3
title_full_unstemmed Temperature sensitive contact modes allosterically gate TRPV3
title_short Temperature sensitive contact modes allosterically gate TRPV3
title_sort temperature sensitive contact modes allosterically gate trpv3
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599574/
https://www.ncbi.nlm.nih.gov/pubmed/37831724
http://dx.doi.org/10.1371/journal.pcbi.1011545
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