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.
Data availability
The cryo-EM density map and coordinate of TRPC3 have been deposited in the Electron Microscopy Data Bank (EMDB) accession number EMD-7620, and in the RCSB Protein Data Bank (PDB) accession code 6CUD.
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Funding
Van Andel Research Institute
- Wei Lu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Fan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of the human lipid-gated cation channel TRPC3
eLife 7:e36852.
https://doi.org/10.7554/eLife.36852
