Cryo-EM structure of TRPC5 at 2.8-Å resolution reveals unique and conserved structural elements essential for channel function

Jingjing Duan; Jian Li; Gui Lan Chen; Yan Ge; Jieyu Liu; Kechen Xie; Xiaogang Peng; Wei Zhou; Jianing Zhong; Yixing Zhang; Jie Xu; Changhu Xue; Bo Liang; Lan Zhu; Wei Liu; Cheng Zhang; Xiao Li Tian; Jianbin Wang; David E. Clapham; Bo Zeng; Zongli Li; Jin Zhang

doi:10.1126/sciadv.aaw7935

Cryo-EM structure of TRPC5 at 2.8-Å resolution reveals unique and conserved structural elements essential for channel function

Jingjing Duan, Jian Li, Gui Lan Chen, Yan Ge, Jieyu Liu, Kechen Xie, Xiaogang Peng, Wei Zhou, Jianing Zhong, Yixing Zhang, Jie Xu, Changhu Xue, Bo Liang, Lan Zhu, Wei Liu, Cheng Zhang, Xiao Li Tian, Jianbin Wang, David E. Clapham, Bo ZengZongli Li, Jin Zhang

Molecular Sciences, School of (SMS)

Research output: Contribution to journal › Article › peer-review

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Abstract

The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-Å resolution cryo–electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.

Original language	English (US)
Article number	eaaw7935
Journal	Science Advances
Volume	5
Issue number	7
DOIs	https://doi.org/10.1126/sciadv.aaw7935
State	Published - Jul 24 2019

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Duan, J., Li, J., Chen, G. L., Ge, Y., Liu, J., Xie, K., Peng, X., Zhou, W., Zhong, J., Zhang, Y., Xu, J., Xue, C., Liang, B., Zhu, L., Liu, W., Zhang, C., Tian, X. L., Wang, J., Clapham, D. E., ... Zhang, J. (2019). Cryo-EM structure of TRPC5 at 2.8-Å resolution reveals unique and conserved structural elements essential for channel function. Science Advances, 5(7), Article eaaw7935. https://doi.org/10.1126/sciadv.aaw7935

Duan, J, Li, J, Chen, GL, Ge, Y, Liu, J, Xie, K, Peng, X, Zhou, W, Zhong, J, Zhang, Y, Xu, J, Xue, C, Liang, B, Zhu, L, Liu, W, Zhang, C, Tian, XL, Wang, J, Clapham, DE, Zeng, B, Li, Z & Zhang, J 2019, 'Cryo-EM structure of TRPC5 at 2.8-Å resolution reveals unique and conserved structural elements essential for channel function', Science Advances, vol. 5, no. 7, eaaw7935. https://doi.org/10.1126/sciadv.aaw7935

@article{4e0c381f9d4e4721a06f276b80e66b2f,

title = "Cryo-EM structure of TRPC5 at 2.8-{\AA} resolution reveals unique and conserved structural elements essential for channel function",

abstract = "The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-{\AA} resolution cryo–electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.",

author = "Jingjing Duan and Jian Li and Chen, {Gui Lan} and Yan Ge and Jieyu Liu and Kechen Xie and Xiaogang Peng and Wei Zhou and Jianing Zhong and Yixing Zhang and Jie Xu and Changhu Xue and Bo Liang and Lan Zhu and Wei Liu and Cheng Zhang and Tian, {Xiao Li} and Jianbin Wang and Clapham, {David E.} and Bo Zeng and Zongli Li and Jin Zhang",

note = "Funding Information: We thank S. Harrison and the Cryo-EM Facility (Harvard Medical School) for use of their microscopes. We thank M. Liao for providing the Python scripts and help in image processing. J.Zhang was supported by the Thousand Young Talents Program of China, the National Natural Science Foundation of China (grant no. 31770795), and the Jiangxi Province Natural Science Foundation (grant no. 20181ACB20014). J.Li was supported by the National Natural Science Foundation of China (grant no. 81402850). Functional studies in this project were supported by the National Natural Science Foundation of China (grant nos. 31300949 to B.Z. and 31300965 to G.-L.C.). Publisher Copyright: Copyright {\textcopyright} 2019 The Authors.",

year = "2019",

month = jul,

day = "24",

doi = "10.1126/sciadv.aaw7935",

language = "English (US)",

volume = "5",

journal = "Science Advances",

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T1 - Cryo-EM structure of TRPC5 at 2.8-Å resolution reveals unique and conserved structural elements essential for channel function

AU - Duan, Jingjing

AU - Li, Jian

AU - Chen, Gui Lan

AU - Ge, Yan

AU - Liu, Jieyu

AU - Xie, Kechen

AU - Peng, Xiaogang

AU - Zhou, Wei

AU - Zhong, Jianing

AU - Zhang, Yixing

AU - Xu, Jie

AU - Xue, Changhu

AU - Liang, Bo

AU - Zhu, Lan

AU - Liu, Wei

AU - Zhang, Cheng

AU - Tian, Xiao Li

AU - Wang, Jianbin

AU - Clapham, David E.

AU - Zeng, Bo

AU - Li, Zongli

AU - Zhang, Jin

N1 - Funding Information: We thank S. Harrison and the Cryo-EM Facility (Harvard Medical School) for use of their microscopes. We thank M. Liao for providing the Python scripts and help in image processing. J.Zhang was supported by the Thousand Young Talents Program of China, the National Natural Science Foundation of China (grant no. 31770795), and the Jiangxi Province Natural Science Foundation (grant no. 20181ACB20014). J.Li was supported by the National Natural Science Foundation of China (grant no. 81402850). Functional studies in this project were supported by the National Natural Science Foundation of China (grant nos. 31300949 to B.Z. and 31300965 to G.-L.C.). Publisher Copyright: Copyright © 2019 The Authors.

PY - 2019/7/24

Y1 - 2019/7/24

N2 - The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-Å resolution cryo–electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.

AB - The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-Å resolution cryo–electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.

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DO - 10.1126/sciadv.aaw7935

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SN - 2375-2548

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JO - Science Advances

JF - Science Advances

IS - 7

M1 - eaaw7935

ER -

Cryo-EM structure of TRPC5 at 2.8-Å resolution reveals unique and conserved structural elements essential for channel function

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