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.
Highlights
The cytosolic free Ca2+ concentration is strictly regulated because calcium is crucial to most cellular processes, from transcription control, to neurotransmitter release, to hormone molecule synthesis (Berridge et al, 2003; Kumar and Thompson, 2011; Sudhof, 2012)
A key component of store-operated calcium entry (SOCE) has been identified as the TRPC channels, which are calcium-permeable, nonselective cation channels belonging to the TRP superfamily (Liu et al, 2003; Zhu et al, 1998; Zhu et al, 1996)
Distinct to the TRPM, TRPV or TRPA channels whose TRP helix and S6 form a continuous alpha helical structure, the TRP helix in TRPC3 is disengaged from the S6, which aligns with the unique gating mechanism of TRPC, perhaps linked to the lipid activation or voltage independence
Summary
The cytosolic free Ca2+ concentration is strictly regulated because calcium is crucial to most cellular processes, from transcription control, to neurotransmitter release, to hormone molecule synthesis (Berridge et al, 2003; Kumar and Thompson, 2011; Sudhof, 2012). Detailed inspection of the TMD in TRPC3 reveals two unique features: a large elbow-like pre-S1 domain harboring a lipid-binding site (lipid 1), and unusually long S3 helix forming an extracellular domain (ECD), along with the S1-S2 linker and S3-S4 linker (Figure 3a, b). A similar pre-S1 elbow structure with lipid-like density has been observed in the Drosophila mechanosensitive channel NOMPC (Jin et al, 2017) We suggest that this lipid site may be crucially linked to channel activation, given its interaction with S4 and the S4-S5 linker. The TRP helix penetrates into the tunnel formed by the S4-S5 linker of the TMD on the top and the LD9 of the linker domain in the intracellular space on the bottom (Figure 4a), showing an apparently disengaged connection to the S6 helix through a loop of the hinge region instead of a continuous alpha helical structure as in TRPM4 (Figure 4b, e).
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