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XB-ART-55533
Nat Commun January 1, 2018; 9 (1): 2302.
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Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels.

Zheng W , Yang X , Hu R , Cai R , Hofmann L , Wang Z , Hu Q , Liu X , Bulkley D , Yu Y , Tang J , Flockerzi V , Cao Y , Cao E , Chen XZ .


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.

PubMed ID: 29899465
PMC ID: PMC5998024
Article link: Nat Commun
Grant support: [+]

Species referenced: Xenopus
Genes referenced: aopep ctrl dtl mcoln3 pkd1 pkd2 pkd2l1 stag1 trpv1

Disease Ontology terms: polycystic kidney disease 1
OMIMs: POLYCYSTIC KIDNEY DISEASE 1 WITH OR WITHOUT POLYCYSTIC LIVER DISEASE; PKD1 [+]

Article Images: [+] show captions
References [+] :
Anyatonwu, Organic cation permeation through the channel formed by polycystin-2. 2005, Pubmed