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Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels.
Zheng, Wang; Yang, Xiaoyong; Hu, Ruikun; Cai, Ruiqi; Hofmann, Laura; Wang, Zhifei; Hu, Qiaolin; Liu, Xiong; Bulkley, David; Yu, Yong; Tang, Jingfeng; Flockerzi, Veit; Cao, Ying; Cao, Erhu; Chen, Xing-Zhen.
Affiliation
  • Zheng W; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei, 430068, China.
  • Yang X; Department of Physiology, Membrane Protein Disease Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
  • Hu R; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
  • Cai R; School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
  • Hofmann L; Department of Physiology, Membrane Protein Disease Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
  • Wang Z; Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, 66421, Germany.
  • Hu Q; Department of Biological Sciences, St. John's University, Queens, NY, 11439, USA.
  • Liu X; Department of Physiology, Membrane Protein Disease Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
  • Bulkley D; Department of Physiology, Membrane Protein Disease Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
  • Yu Y; Keck Advanced Microscopy Laboratory and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94143, USA.
  • Tang J; Department of Biological Sciences, St. John's University, Queens, NY, 11439, USA.
  • Flockerzi V; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei, 430068, China. jingfeng9930@163.com.
  • Cao Y; Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, 66421, Germany.
  • Cao E; School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
  • Chen XZ; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA. erhu.cao@biochem.utah.edu.
Nat Commun ; 9(1): 2302, 2018 06 13.
Article in En | MEDLINE | ID: mdl-29899465
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Calcium Channels / Polycystic Kidney, Autosomal Dominant / Receptors, Cell Surface / TRPP Cation Channels Limits: Animals / Female / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2018 Type: Article Affiliation country: China
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Calcium Channels / Polycystic Kidney, Autosomal Dominant / Receptors, Cell Surface / TRPP Cation Channels Limits: Animals / Female / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2018 Type: Article Affiliation country: China