RT Journal Article
SR Electronic
T1 The contribution of the ankyrin repeat domain of TRPV1 as a thermal module
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 641803
DO 10.1101/641803
A1 E. Ladrón-de-Guevara
A1 G. E. Rangel-Yescas
A1 D. A. Fernández-Velasco
A1 A. Torres-Larios
A1 T. Rosenbaum
A1 L. D. Islas
YR 2019
UL http://biorxiv.org/content/early/2019/05/19/641803.abstract
AB The TRPV1 cation non-selective ion channel plays an essential role in thermosensation and perception of other noxious stimuli. TRPV1 can be activated by low pH, high temperature or naturally occurring pungent molecules such as allicin, capsaicin or resiniferatoxin. Its noxious thermal sensitivity makes it an important participant as a thermal sensor in mammals. However, details of the mechanism of channel activation by increases in temperature remain unclear. Here we used a combination of approaches to try to understand the role of the ankyrin repeat domain (ARD) in channel behavior. First, a computational modeling approach by coarse-grained molecular dynamics simulation of the whole TRPV1 embedded in a phosphatidylcholine (POPC) and phosphatidylethanolamine (POPE) membrane provides insight into the dynamics of this channel domain. Global analysis of the structural ensemble shows that the ankyrin repeat domain is a region that sustains high fluctuations during dynamics at different temperatures. We then performed biochemical and thermal stability studies of the purified ARD by means of circular dichroism and tryptophan fluorescence and demonstrate that this region undergoes structural changes at similar temperatures that lead to TRPV1 activation. Our data suggest that the ARD is a dynamic module and that it may participate in controlling the temperature sensitivity of TRPV1.Statement of Significance This work demonstrates that the temperature-dependent dynamics of the ankyrin repeat domain (ARD) of TRPV1 channels, as probed by coarse-grained molecular dynamics, corresponds to the experimentally determined dynamics of an isolated ARD domain. These results show that this region of TRPV1 channels undergoes significant conformational change as a function of increased temperature and suggest that it participates in the temperature-dependent structural changes that lead to channel opening.