Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29899465.
- Also identified by DOI 10.1038/s41467-018-04586-x and PMC identifier 5998024.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Calcium Channels
- Polycystic Kidney, Autosomal Dominant
- Receptors, Cell Surface
- TRPP Cation Channels