PUBLICATION
Structure of the carboxy-terminal region of a KCNH channel
- Authors
- Brelidze, T.I., Carlson, A.E., Sankaran, B., and Zagotta, W.N.
- ID
- ZDB-PUB-120111-38
- Date
- 2012
- Source
- Nature 481(7382): 530-533 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites
- Crystallography, X-Ray
- Electrophysiological Phenomena
- Ether-A-Go-Go Potassium Channels/chemistry*
- Ether-A-Go-Go Potassium Channels/genetics
- Ether-A-Go-Go Potassium Channels/metabolism
- Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
- Ion Channels/chemistry
- Models, Molecular
- Mutation
- Protein Structure, Quaternary
- Protein Structure, Tertiary
- Static Electricity
- Structure-Activity Relationship
- Zebrafish
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 22230959 Full text @ Nature
Citation
Brelidze, T.I., Carlson, A.E., Sankaran, B., and Zagotta, W.N. (2012) Structure of the carboxy-terminal region of a KCNH channel. Nature. 481(7382):530-533.
Abstract
The KCNH family of ion channels, comprising ether-à-go-go (EAG), EAG-related gene (ERG), and EAG-like (ELK) K+-channel subfamilies, is crucial for repolarization of the cardiac action potential1, regulation of neuronal excitability2 and proliferation of tumour cells3. The carboxy-terminal region of KCNH channels contains a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore4. The C-linker/CNBHD is essential for proper function and trafficking of ion channels in the KCNH family5, 6, 7, 8, 9. However, despite the importance of the C-linker/CNBHD for the function of KCNH channels, the structural basis of ion-channel regulation by the C-linker/CNBHD is unknown. Here we report the crystal structure of the C-linker/CNBHD of zebrafish ELK channels at 2.2-Å resolution. Although the overall structure of the C-linker/CNBHD of ELK channels is similar to the cyclic-nucleotide-binding domain (CNBD) structure of the related hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channels10, there are marked differences. Unlike the CNBD of HCN, the CNBHD of ELK displays a negatively charged electrostatic profile that explains the lack of binding and regulation of KCNH channels by cyclic nucleotides4, 11. Instead of cyclic nucleotide, the binding pocket is occupied by a short β-strand. Mutations of the β-strand shift the voltage dependence of activation to more depolarized voltages, implicating the β-strand as an intrinsic ligand for the CNBHD of ELK channels. In both ELK and HCN channels the C-linker is the site of virtually all of the intersubunit interactions in the C-terminal region. However, in the zebrafish ELK structure there is a reorientation in the C-linker so that the subunits form dimers instead of tetramers, as observed in HCN channels. These results provide a structural framework for understanding the regulation of ion channels in the KCNH family by the C-linker/CNBHD and may guide the design of specific drugs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping