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. [email protected].
  • 9. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA. [email protected].
  • 10. National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei, 430068, China. [email protected].
  • 11. Department of Physiology, Membrane Protein Disease Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada. [email protected].
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.