title: C-terminal β9-strand of the cyclic nucleotide-binding homology domain stabilizes activated states of Kv11.1 channels.
abstract: Kv11.1 potassium channels are important for regulation of the normal rhythm of the heartbeat. Reduced activity of Kv11.1 channels causes long QT syndrome type 2, a disorder that increases the risk of cardiac arrhythmias and sudden cardiac arrest. Kv11.1 channels are members of the KCNH subfamily of voltage-gated K(+) channels. However, they also share many similarities with the cyclic nucleotide gated ion channel family, including having a cyclic nucleotide-binding homology (cNBH) domain. Kv11.1 channels, however, are not directly regulated by cyclic nucleotides. Recently, crystal structures of the cNBH domain from mEAG and zELK channels, both members of the KCNH family of voltage-gated potassium channels, revealed that a C-terminal β9-strand in the cNBH domain occupied the putative cyclic nucleotide-binding site thereby precluding binding of cyclic nucleotides. Here we show that mutations to residues in the β9-strand affect the stability of the open state relative to the closed state of Kv11.1 channels. We also show that disrupting the structure of the β9-strand reduces the stability of the inactivated state relative to the open state. Clinical mutations located in this β9-strand result in reduced trafficking efficiency, which suggests that binding of the C-terminal β9-strand to the putative cyclic nucleotide-binding pocket is also important for assembly and trafficking of Kv11.1 channels.
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia ; St Vincent's Clinical School, University of New South Wales, New South Wales, Australia.
authors.forename: Chai Ann
authors.initials: CA
authors.lastname: Ng
authors.forename: Ying
authors.initials: Y
authors.lastname: Ke
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Perry
authors.forename: Peter S
authors.initials: PS
authors.lastname: Tan
authors.forename: Adam P
authors.initials: AP
authors.lastname: Hill
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D009712:Nucleotides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009712:Nucleotides, Cyclic