Structure of the human lipid-gated cation channel TRPC3.

The TRPC channels are crucially involved in store-operated calcium entry and calcium homeostasis， and they are implicated in human diseases such as neurodegenerative disease， cardiac hypertrophy， and spinocerebellar ataxia. We present a structure of the full-length human TRPC3， a lipid-gated TRPC member， in a lipid-occupied， closed state at 3.3 Angstrom. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to， and thus disengaged from， the pore-lining S6， suggesting a different gating mechanism from other TRP subfamily channels. The third transmembrane helix S3 is remarkably long， shaping a unique transmembrane domain， and constituting an extracellular domain that may serve as a sensor of external stimuli. We identified two lipid-binding sites， one being sandwiched between the pre-S1 elbow and the S4-S5 linker， and the other being close to the ion-conducting pore， where the conserved LWF motif of the TRPC family is located.