Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels

Nat Commun. 2018 Jun 13;9(1):2302. doi: 10.1038/s41467-018-04586-x.

Wang Zheng ¹ ², Xiaoyong Yang ³, Ruikun Hu ⁴, Ruiqi Cai ², Laura Hofmann ⁵, Zhifei Wang ⁶, Qiaolin Hu ², Xiong Liu ², David Bulkley ⁷, Yong Yu ⁶, Jingfeng Tang ⁸, Veit Flockerzi ⁵, Ying Cao ⁴, Erhu Cao ⁹, Xing-Zhen Chen ¹⁰ ¹¹

Affiliations

1 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei, 430068, China.
2 Department of Physiology, Membrane Protein Disease Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
3 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
4 School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
5 Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, 66421, Germany.
6 Department of Biological Sciences, St. John's University, Queens, NY, 11439, USA.
7 Keck Advanced Microscopy Laboratory and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94143, USA.
8 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei, 430068, China. jingfeng9930@163.com.
9 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA. erhu.cao@biochem.utah.edu.
10 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei, 430068, China. xzchen@ualberta.ca.
11 Department of Physiology, Membrane Protein Disease Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada. xzchen@ualberta.ca.

PMID: 29899465 DOI: 10.1038/s41467-018-04586-x

Abstract

PKD2 and PKD1 genes are mutated in human autosomal dominant polycystic kidney disease. PKD2 can form either a homomeric cation channel or a heteromeric complex with the PKD1 receptor, presumed to respond to ligand(s) and/or mechanical stimuli. Here, we identify a two-residue hydrophobic gate in PKD2L1, and a single-residue hydrophobic gate in PKD2. We find that a PKD2 gain-of-function gate mutant effectively rescues PKD2 knockdown-induced phenotypes in embryonic zebrafish. The structure of a PKD2 activating mutant F604P by cryo-electron microscopy reveals a π- to α-helix transition within the pore-lining helix S6 that leads to repositioning of the gate residue and channel activation. Overall the results identify hydrophobic gates and a gating mechanism of PKD2 and PKD2L1.

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