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
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
Figures
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Mutations / Transgenics
Human Disease / Model
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