Symmetry transitions during gating of the TRPV2 ion channel in lipid membranes

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Abstract

The Transient Receptor Potential Vanilloid 2 (TRPV2) channel is a member of the temperature-sensing thermoTRPV family. Recent advances in cryo-electronmicroscopy (cryo-EM) and X-ray crystallography have provided many important insights into the gating mechanisms of thermoTRPV channels. Interestingly, crystallographic studies of ligand-dependent TRPV2 gating have shown that the TRPV2 channel adopts two-fold symmetric arrangements during the gating cycle. However, it was unclear if crystal packing forces played a role in stabilizing the two-fold symmetric arrangement of the channel. Here we employ cryo-EM to elucidate the structure of full-length rabbit TRPV2 in complex with the agonist resiniferatoxin (RTx) in nanodiscs and amphipol. We show that RTx induces two-fold symmetric conformations of TRPV2 in both environments. However, the two-fold symmetry is more pronounced in the native-like lipid environment of the nanodiscs. Our data offers insights into a gating pathway in TRPV2 involving symmetry transitions.

Data availability

The EM maps and atomic models have been deposited with the Electron Microscopy Data Bank (accession numbers EMD-20143, EMD-20145, EMD-20146, and EMD-20148) and the Protein Data Back (entry codes 6OO3, 6OO4, 6OO5, and 6OO7), respectively.

The following data sets were generated

1. Zubcevic L
2. Hsu AL
3. Borgnia MJ
4. Lee S-Y
(2019) Cryo-EM structure of the C4-symmetric TRPV2/RTx complex in amphipol resolved to 2.9 A
Electron Microscopy Data Bank, EMD-20143.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-20143
1. Zubcevic L
2. Hsu AL
3. Borgnia MJ
4. Lee S-Y
(2019) Cryo-EM structure of the C2-symmetric TRPV2/RTx complex in amphipol resolved to 3.3 A
Electron Microscopy Data Bank, EMD-20145.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-20145
1. Zubcevic L
2. Hsu AL
3. Borgnia MJ
4. Lee S-Y
(2019) Cryo-EM structure of the C2-symmetric TRPV2/RTx complex in amphipol resolved to 4.2 A
Electron Microscopy Data Bank, EMD-20146.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-20146
1. Zubcevic L
2. Hsu AL
3. Borgnia MJ
4. Lee S-Y
(2019) Cryo-EM structure of the C2-symmetric TRPV2/RTx complex in nanodiscs
Electron Microscopy Data Bank, EMD-20148.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-20148
1. Zubcevic L
2. Hsu AL
3. Borgnia MJ
4. Lee S-Y
(2019) Cryo-EM structure of the C4-symmetric TRPV2/RTx complex in amphipol resolved to 2.9 A
Protein Data Bank, 6OO3.

http://www.rcsb.org/structure/6OO3
1. Zubcevic L
2. Hsu AL
3. Borgnia MJ
4. Lee S-Y
(2019) Cryo-EM structure of the C2-symmetric TRPV2/RTx complex in amphipol resolved to 3.3 A
Protein Data Bank, 6OO4.

http://www.rcsb.org/structure/6OO4
1. Zubcevic L
2. Hsu AL
3. Borgnia MJ
4. Lee S-Y
(2019) Cryo-EM structure of the C2-symmetric TRPV2/RTx complex in amphipol resolved to 4.2 A
Protein Data Bank, 6OO5.

http://www.rcsb.org/structure/6OO5
1. Zubcevic L
2. Hsu AL
3. Borgnia MJ
4. Lee S-Y
(2019) Cryo-EM structure of the C2-symmetric TRPV2/RTx complex in nanodiscs
Protein Data Bank, 6OO7.

http://www.rcsb.org/structure/6OO7

Article and author information

Author details

Lejla Zubcevic

Department of Biochemistry, Duke University School of Medicine, Durham, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1884-9235
Allen L Hsu

Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2065-3802
Mario J Borgnia

Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States

Competing interests
The authors declare that no competing interests exist.
Seok-Yong Lee

Department of Biochemistry, Duke University School of Medicine, Durham, United States

For correspondence
seok-yong.lee@duke.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0662-9921

Funding

National Institute of Neurological Disorders and Stroke (R35NS097241)

Seok-Yong Lee

National Institute of Environmental Health Sciences (ZIC ES103326)

Meario J Borgnia

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

Copyright

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.