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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Animals
  • Calcium Channels / chemistry
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Cryoelectron Microscopy
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ion Channel Gating
  • Models, Molecular
  • Mutation
  • Polycystic Kidney, Autosomal Dominant / genetics
  • Polycystic Kidney, Autosomal Dominant / metabolism*
  • Protein Conformation
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • TRPP Cation Channels / chemistry
  • TRPP Cation Channels / genetics
  • TRPP Cation Channels / metabolism*
  • Xenopus
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism
  • Zebrafish Proteins / antagonists & inhibitors
  • Zebrafish Proteins / genetics

Substances

  • Calcium Channels
  • Carrier Proteins
  • PKD2 protein, zebrafish
  • PKD2L1 protein, human
  • Receptors, Cell Surface
  • Recombinant Proteins
  • TRPP Cation Channels
  • Zebrafish Proteins
  • polycystic kidney disease 1 protein
  • polycystic kidney disease 2 protein