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
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/genetics
  • Protein Conformation
  • Carrier Proteins/antagonists & inhibitors
  • Carrier Proteins/genetics
  • Polycystic Kidney, Autosomal Dominant/genetics
  • Polycystic Kidney, Autosomal Dominant/metabolism*
  • Humans
  • Models, Molecular
  • Gene Knockdown Techniques
  • Cryoelectron Microscopy
  • TRPP Cation Channels/chemistry
  • TRPP Cation Channels/genetics
  • TRPP Cation Channels/metabolism*
  • Calcium Channels/chemistry
  • Calcium Channels/genetics
  • Calcium Channels/metabolism*
  • Allosteric Regulation
  • Amino Acid Sequence
  • Hydrophobic and Hydrophilic Interactions
  • Ion Channel Gating
  • Animals
  • Female
  • Receptors, Cell Surface/chemistry
  • Receptors, Cell Surface/genetics
  • Receptors, Cell Surface/metabolism*
  • Recombinant Proteins/chemistry
  • Recombinant Proteins/genetics
  • Recombinant Proteins/metabolism
  • Mutation
  • Xenopus
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
(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 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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-145 .
Genes / Markers
Figures
Figure Gallery (1 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
AB + MO3-pkd2standard conditionsProtruding-mouth
AB + MO3-pkd2standard conditionsProtruding-mouth
AB + MO3-pkd2standard conditionsProtruding-mouth
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Mutations / Transgenics
No data available
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
No data available
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.