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
-
- Female
- Receptors, Cell Surface/chemistry
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism*
- Ion Channel Gating
- Protein Conformation
- Xenopus
- Carrier Proteins/antagonists & inhibitors
- Carrier Proteins/genetics
- Animals
- Polycystic Kidney, Autosomal Dominant/genetics
- Polycystic Kidney, Autosomal Dominant/metabolism*
- Hydrophobic and Hydrophilic Interactions
- Recombinant Proteins/chemistry
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Humans
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics
- Gene Knockdown Techniques
- Amino Acid Sequence
- Cryoelectron Microscopy
- Calcium Channels/chemistry
- Calcium Channels/genetics
- Calcium Channels/metabolism*
- Mutation
- TRPP Cation Channels/chemistry
- TRPP Cation Channels/genetics
- TRPP Cation Channels/metabolism*
- Allosteric Regulation
- Models, Molecular
- PubMed
- 29899465 Full text @ Nat. Commun.
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping