TRPV2 Ion Channel Gating Through Allosteric Domain Coupling Revealed by Cryo-EM

Abstract

Cation channels of the TRP family serve important physiological roles by opening in response to diverse intra- and extra-cellular stimuli which regulate their lower or upper gates. Despite extensive studies, the mechanism which couples these gates has remained obscure. Previous structures have failed to resolve extracellular loops, known in the TRPV subfamily as the “pore turret,” which are proximal to the upper gate domains. We establish the importance of the pore turret through activity assays and by solving structures of TRPV2 both with and without this domain intact at resolutions of 4.0 A and 3.6 A respectively. These structures resolve the full length pore turret and reveal fully open and closed states of TRPV2 with an unoccupied vanilloid pocket. Our results reveal how physiological signals, such as PIP2 binding, can regulate the lower gate and couple to the upper gate through a mechanism facilitated by the pore turret.