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

Wang Zheng, Xiaoyong Yang, Ruikun Hu, Ruiqi Cai, Laura Hofmann, Zhifei Wang, Qiaolin Hu, Xiong Liu, David Bulkley, Yong Yu, Jingfeng Tang (), Veit Flockerzi, Ying Cao, Erhu Cao () and Xing-Zhen Chen ()
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Wang Zheng: Hubei University of Technology
Xiaoyong Yang: University of Utah School of Medicine
Ruikun Hu: Tongji University
Ruiqi Cai: University of Alberta
Laura Hofmann: Universität des Saarlandes
Zhifei Wang: St. John’s University
Qiaolin Hu: University of Alberta
Xiong Liu: University of Alberta
David Bulkley: University of California, San Francisco
Yong Yu: St. John’s University
Jingfeng Tang: Hubei University of Technology
Veit Flockerzi: Universität des Saarlandes
Ying Cao: Tongji University
Erhu Cao: University of Utah School of Medicine
Xing-Zhen Chen: Hubei University of Technology

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04586-x

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