PUBLICATION
Atomic Structure of the Cystic Fibrosis Transmembrane Conductance Regulator
- Authors
- Zhang, Z., Chen, J.
- ID
- ZDB-PUB-161204-8
- Date
- 2016
- Source
- Cell 167: 1586-1597.e9 (Journal)
- Registered Authors
- Keywords
- ABC transporter, CFTR, anion channel, atomic structure, cryo-EM
- MeSH Terms
-
- Animals
- Cryoelectron Microscopy
- Cystic Fibrosis/genetics
- Cystic Fibrosis/metabolism
- Cystic Fibrosis Transmembrane Conductance Regulator/chemistry*
- Cystic Fibrosis Transmembrane Conductance Regulator/genetics
- Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
- Humans
- Models, Molecular
- Mutation
- Protein Folding
- Sequence Homology, Amino Acid
- Zebrafish/metabolism*
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/metabolism
- PubMed
- 27912062 Full text @ Cell
Citation
Zhang, Z., Chen, J. (2016) Atomic Structure of the Cystic Fibrosis Transmembrane Conductance Regulator. Cell. 167:1586-1597.e9.
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from the ATP-binding cassette (ABC) transporter family. In this study, we determined the structure of zebrafish CFTR in the absence of ATP by electron cryo-microscopy to 3.7 Å resolution. Human and zebrafish CFTR share 55% sequence identity, and 42 of the 46 cystic-fibrosis-causing missense mutational sites are identical. In CFTR, we observe a large anion conduction pathway lined by numerous positively charged residues. A single gate near the extracellular surface closes the channel. The regulatory domain, dephosphorylated, is located in the intracellular opening between the two nucleotide-binding domains (NBDs), preventing NBD dimerization and channel opening. The structure also reveals why many cystic-fibrosis-causing mutations would lead to defects either in folding, ion conduction, or gating and suggests new avenues for therapeutic intervention.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping