Cryo-EM structure of the cytoplasmic domain of murine transient receptor potential cation channel subfamily C member 6 (TRPC6)

摘要: The kidney maintains the internal milieu by regulating retention and excretion of proteins, ions, small molecules. glomerular podocyte forms slit diaphragm ultrafiltration filter, whose damage leads to progressive failure focal segmental glomerulosclerosis (FSGS). canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocyte, mutations its cytoplasmic domain cause FSGS humans. In vitro evaluation disease-causing TRPC6 has revealed that these genetic alterations result abnormal gating. However, mechanism whereby modulates function largely unknown. Here, we report a cryo-EM structure murine at 3.8 A resolution. fold characterized an inverted dome-like chamber pierced four radial horizontal helices converge into vertical coiled-coil central axis. Unlike other TRP channels, displays unique swap occurs junction coiled-coil. Multiple buried interface between ankyrin repeats, which form dome, suggesting regions are critical for allosteric gating modulation. This functionally target drug design. Importantly, dysfunction family members learning deficits (TRPC1/4/5) ataxia (TRPC3). Our data provide structural framework mechanistic investigation TRPC family.