@article{c078b55f5a7f45b59e746c07f30a3b1f,
title = "A folding reaction at the C-terminal domain drives temperature sensing in TRPM8 channels",
abstract = "In mammals, temperature-sensitive TRP channels make membrane conductance of cells extremely temperature dependent, allowing the detection of temperature ranging from noxious cold to noxious heat. We progressively deleted the distal carboxyl terminus domain (CTD) of the cold-activated melastatin receptor channel, TRPM8. We found that the enthalpy change associated with channel gating is proportional to the length of the CTD. Deletion of the last 36 amino acids of the CTD transforms TRPM8 into a reduced temperature-sensitivity channel (Q10 ∼4). Exposing the intracellular domain to a denaturing agent increases the energy required to open the channel indicating that cold drives channel gating by stabilizing the folded state of the CTD. Experiments in the presence of an osmoticant agent suggest that channel gating involves a change in solute-inaccessible volume in the CTD of ∼1,900 {\AA}3 This volume matches the void space inside the coiled coil according to the cryogenic electron microscopy structure of TRPM8. The results indicate that a folding-unfolding reaction of a specialized temperature-sensitive structure is coupled to TRPM8 gating.",
keywords = "coiled coil, heat capacity, protein folding, temperature sensor, TRPM8",
author = "Ignacio D{\'i}az-Franulic and Natalia Raddatz and Karen Castillo and Gonz{\'a}lez-Nilo, {Fernando D.} and Ramon Latorre",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Christopher Miller and John Ewer for comments on the manuscript and Mrs. Luisa Soto, Mr. Patricio Farias, and Mrs. Victoria Prado (Universidad de Valparaiso) for their excellent technical assistance. This research was supported by the Fondo Nacional de Desarrollo Cient{\'i}fico y Tecnol{\'o}gico (FONDECYT) Regular 1190203 (to R.L.), 1170733 (to F.G.-N.), and 1180999 (to K.C.) and FONDECYT Postdoctorado 3170599 (to I.D.-F.), Proyecto PAI7719087 (to I.D.-F.); US Army Research Office Cooperative Agreement W911NF-17-2-0081 (to F.G.-N.); and US Air Force Office of Scientific Research grant under award FA9550-16-1-0384 (R.L.). The Centro Interdisciplinario de Neurociencias de Valparaiso (CINV) is a Millennium Institute supported by the Iniciativa Cient{\'i}fica Milenio-Agencia Nacional de Investigaci{\'o}n y Desarrollo (ICM-ANID), Project P09-022-F, CINV. Funding Information: We thank Christopher Miller and John Ewer for comments on the manuscript and Mrs. Luisa Soto, Mr. Patricio Farias, and Mrs. Victoria Prado (Universidad de Valparaiso) for their excellent technical assistance. This research was supported by the Fondo Nacional de Desarrollo Cient?fico y Tecnol?gico (FONDECYT) Regular 1190203 (to R.L.), 1170733 (to F.G.-N.), and 1180999 (to K.C.) and FONDECYT Postdoctorado 3170599 (to I.D.-F.), Proyecto PAI7719087 (to I.D.-F.); US Army Research Office Cooperative Agreement W911NF-17-2-0081 (to F.G.-N.); and US Air Force Office of Scientific Research grant under award FA9550-16-1-0384 (R.L.). The Centro Interdisciplinario de Neurociencias de Valparaiso (CINV) is a Millennium Institute supported by the Iniciativa Cient?fica Milenio-Agencia Nacional de Investigaci?n y Desarrollo (ICM-ANID), Project P09-022-F, CINV. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = aug,
day = "18",
doi = "10.1073/pnas.2004303117",
language = "English",
volume = "117",
pages = "20298--20304",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "33",
}