PUBLICATION

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

Authors
Zheng, W., Yang, X., Hu, R., Cai, R., Hofmann, L., Wang, Z., Hu, Q., Liu, X., Bulkey, D., Yu, Y., Tang, J., Flockerzi, V., Cao, Y., Cao, E., Chen, X.Z.
ID
ZDB-PUB-180615-7
Date
2018
Source
Nature communications   9: 2302 (Journal)
Registered Authors
Cao, Ying
Keywords
none
MeSH Terms
  • Cryoelectron Microscopy
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/genetics
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Xenopus
  • Female
  • Mutation
  • Recombinant Proteins/chemistry
  • Recombinant Proteins/genetics
  • Recombinant Proteins/metabolism
  • Animals
  • Receptors, Cell Surface/chemistry
  • Receptors, Cell Surface/genetics
  • Receptors, Cell Surface/metabolism*
  • Gene Knockdown Techniques
  • Protein Conformation
  • TRPP Cation Channels/chemistry
  • TRPP Cation Channels/genetics
  • TRPP Cation Channels/metabolism*
  • Carrier Proteins/antagonists & inhibitors
  • Carrier Proteins/genetics
  • Humans
  • Ion Channel Gating
  • Hydrophobic and Hydrophilic Interactions
  • Allosteric Regulation
  • Calcium Channels/chemistry
  • Calcium Channels/genetics
  • Calcium Channels/metabolism*
  • Models, Molecular
  • Polycystic Kidney, Autosomal Dominant/genetics
  • Polycystic Kidney, Autosomal Dominant/metabolism*
  • Amino Acid Sequence
(all 34)
PubMed
29899465 Full text @ Nat. Commun.
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 ?- to ?-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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-145 .
Genes / Markers
Figures
Figure Gallery (1 images)
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Zheng, W., Yang, X., Hu, R., Cai, R., Hofmann, L., Wang, Z., Hu, Q., Liu, X., Bulkey, D., Yu, Y., Tang, J., Flockerzi, V., Cao, Y., Cao, E., Chen, X.Z. (2018) Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels. Nature communications. 9:2302.