XB-ART-54633Nat Struct Mol Biol. February 26, 2018;
Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms.
The transient receptor potential (TRP) channel TRPV4 participates in multiple biological processes, and numerous TRPV4 mutations underlie several distinct and devastating diseases. Here we present the cryo-EM structure of Xenopus tropicalis TRPV4 at 3.8-Å resolution. The ion-conduction pore contains an intracellular gate formed by the inner helices, but lacks any extracellular gate in the selectivity filter, as observed in other TRPV channels. Anomalous X-ray diffraction analyses identify a single ion-binding site in the selectivity filter, thus explaining TRPV4 nonselectivity. Structural comparisons with other TRP channels and distantly related voltage-gated cation channels reveal an unprecedented, unique packing interface between the voltage-sensor-like domain and the pore domain, suggesting distinct gating mechanisms. Moreover, our structure begins to provide mechanistic insights to the large set of pathogenic mutations, offering potential opportunities for drug development.
PubMed ID: 29483651
Article link: Nat Struct Mol Biol.
Grant support: P30 CA008748 NCI NIH HHS
Genes referenced: trpv4
OMIMs referenced: BRACHYOLMIA TYPE 3
External Resources: GO Terms referenced: voltage-gated cation channel activity