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

被引：77

作者：

Duan, Jingjing ^{[1
,2
,3
]}

Li, Jian ^{[4
,5
]}

Chen, Gui-Lan ^{[6
,7
,8
]}

Ge, Yan ^{[6
,7
]}

Liu, Jieyu ^{[6
,7
]}

Xie, Kechen ^{[6
,7
]}

Peng, Xiaogang ^{[9
]}

Zhou, Wei ^{[9
]}

Zhong, Jianing ^{[5
]}

Zhang, Yixing ^{[2
]}

Xu, Jie ^{[10
]}

Xue, Changhu ^{[10
]}

Liang, Bo ^{[11
]}

Zhu, Lan ^{[12
]}

Liu, Wei ^{[12
]}

Zhang, Cheng ^{[13
]}

Tian, Xiao-Li ^{[1
]}

Wang, Jianbin ^{[2
]}

Clapham, David E. ^{[3
]}

Zeng, Bo ^{[6
,7
,8
]}

Li, Zongli ^{[14
]}

Zhang, Jin ^{[2
]}

机构：

[1] Nanchang Univ, Sch Life Sci, HARI, Nanchang 330031, Jiangxi, Peoples R China

[2] Nanchang Univ, Sch Basic Med Sci, Nanchang 330031, Jiangxi, Peoples R China

[3] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA

[4] Gannan Med Univ, Minist Educ, Key Lab Prevent & Treatment Cardiovasc & Cerebrov, Ganzhou 341000, Peoples R China

[5] Gannan Med Univ, Coll Pharmaceut Sci, 1 Yixueyuan Rd, Ganzhou 341000, Jiangxi, Peoples R China

[6] Southwest Med Univ, Minist Educ & Sichuan Prov, Key Lab Med Electrophysiol, Luzhou 646000, Sichuan, Peoples R China

[7] Southwest Med Univ, Inst Cardiovasc Res, Luzhou 646000, Sichuan, Peoples R China

[8] Southwest Med Univ, Affiliated Hosp, Dept Endocrinol, Luzhou 646000, Sichuan, Peoples R China

[9] Nanchang Univ, Affiliated Hosp 2, Key Lab Mol Med, Nanchang 330006, Jiangxi, Peoples R China

[10] Ocean Univ China, Coll Food Sci & Engn, Qingdao 266003, Shandong, Peoples R China

[11] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA

[12] Arizona State Univ, Biodesign Inst, Ctr Appl Struct Discovery, Sch Mol Sci & Biodesign, Tempe, AZ 85287 USA

[13] Jiangxi Jmerry Biopharmaceut Co Ltd, Ganzhou 341000, Jiangxi, Peoples R China

[14] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Howard Hughes Med Inst, Boston, MA 02115 USA

来源：

SCIENCE ADVANCES | 2019年 / 5卷 / 07期

基金：

中国国家自然科学基金;

关键词：

RECEPTOR POTENTIAL CHANNELS; ION-CHANNEL; TRPV1; STRUCTURES; CATION CHANNEL; ACTIVATION; MECHANISMS; PROTEINS; AMYGDALA;

D O I：

10.1126/sciadv.aaw7935

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-angstrom 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.

引用

页数：12

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