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

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. Mutations in the cation channel PKD2 cause human autosomal dominant polycystic kidney disease but its channel function and gating mechanism are poorly understood. Here authors study PKD2 using electrophysiology and cryo-EM, which identifies hydrophobic gates and proposes a gating mechanism for PKD2.