title: Structure of the Cyclic Nucleotide-Binding Homology Domain of the hERG Channel and Its Insight into Type 2 Long QT Syndrome.
abstract: The human ether-à-go-go related gene (hERG) channel is crucial for the cardiac action potential by contributing to the fast delayed-rectifier potassium current. Mutations in the hERG channel result in type 2 long QT syndrome (LQT2). The hERG channel contains a cyclic nucleotide-binding homology domain (CNBHD) and this domain is required for the channel gating though molecular interactions with the eag domain. Here we present solution structure of the CNBHD of the hERG channel. The structural study reveals that the CNBHD adopts a similar fold to other KCNH channels. It is self-liganded and it contains a short β-strand that blocks the nucleotide-binding pocket in the β-roll. Folding of LQT2-related mutations in this domain was shown to be affected by point mutation. Mutations in this domain can cause protein aggregation in E. coli cells or induce conformational changes. One mutant-R752W showed obvious chemical shift perturbation compared with the wild-type, but it still binds to the eag domain. The helix region from the N-terminal cap domain of the hERG channel showed unspecific interactions with the CNBHD.
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Hui Qi
authors.initials: HQ
authors.lastname: Ng
authors.affiliation: Institute of Chemical &Engineering Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Qingxin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: CongBao
authors.initials: C
authors.lastname: Kang
mesh_terms: D001665:Binding Sites; D000072237:ERG1 Potassium Channel / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008133:Long QT Syndrome / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense; D017354:Point Mutation; D000072756:Protein Conformation, alpha-Helical; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D012996:Solutions
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D012996:Solutions