Regulatory switch at the cytoplasmic interface controls TRPV channel gating
Temperature-sensitive transient receptor potential vanilloid (thermoTRPV) channels are activated by ligands and heat, and are involved in various physiological processes. ThermoTRPV channels possess a large cytoplasmic ring consisting of N-terminal ankyrin repeat domains (ARD) and C-terminal domains (CTD). The cytoplasmic inter-protomer interface is unique and consists of a CTD coiled around a b-sheet which makes contacts with the neighboring ARD. Despite much existing evidence that the cytoplasmic ring is important for thermoTRPV function, the mechanism by which this unique structure is involved in thermoTRPV gating has not been clear. Here we present cryo-EM and electrophysiological studies which demonstrate that TRPV3 gating involves large rearrangements at the cytoplasmic inter-protomer interface and that this motion triggers coupling between cytoplasmic and transmembrane domains, priming the channel for opening. Furthermore, our studies unveil the role of this interface in the distinct biophysical and physiological properties of individual thermoTRPV subtypes.
Cryo-EM data and structural models are deposited in the EMDB and RCSB, respectively with the following codes: EMD-20192, PDB: 6OT2 and EMD-20194, PDB: 6OT5
Structure of the TRPV3 K169A sensitized mutant in apo form at 4.1 A resolutionProtein Data, Bank, 6OT2.
Article and author information
National Institute of Neurological Disorders and Stroke (R35NS097241)
- Seok-Yong Lee
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Kenton Jon Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
- Received: April 16, 2019
- Accepted: May 8, 2019
- Accepted Manuscript published: May 9, 2019 (version 1)
- Version of Record published: May 28, 2019 (version 2)
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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