Structure of the human lipid-gated cation channel TRPC3

Elife. 2018 May 4;7:e36852. doi: 10.7554/eLife.36852.

Abstract

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.

Keywords: cryo-EM; human; ion channel; lipid-sensitive; molecular biophysics; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cryoelectron Microscopy
  • Humans
  • Lipid Metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Domains
  • TRPC Cation Channels / chemistry
  • TRPC Cation Channels / metabolism
  • TRPC Cation Channels / ultrastructure*

Substances

  • TRPC Cation Channels
  • TRPC3 cation channel

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.