Structure of the carboxy-terminal region of a KCNH channel

Article

关键词: LONG-QT SYNDROME;    FUNCTIONAL-PROPERTIES;    POTASSIUM CHANNELS;    HERG;    ACTIVATION;    DOMAIN;    VALIDATION;   

DOI  :  10.1038/nature10735

来源: SCIE

【 摘 要 】

The KCNH family of ion channels, comprising ether-a-go-go (EAG), EAG-related gene (ERG), and EAG-like (ELK) K+-channel subfamilies, is crucial for repolarization of the cardiac action potential(1), regulation of neuronal excitability(2) and proliferation of tumour cells(3). The carboxy-terminal region of KCNH channels contains a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore(4). The C-linker/CNBHD is essential for proper function and trafficking of ion channels in the KCNH family(5-9). 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-angstrom 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) channels(10), 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 nucleotides(4,11). Instead of cyclic nucleotide, the binding pocket is occupied by a short beta-strand. Mutations of the beta-strand shift the voltage dependence of activation to more depolarized voltages, implicating the beta-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.

【 授权许可】

Free