title: Structure of the HERG K+ channel S5P extracellular linker: role of an amphipathic alpha-helix in C-type inactivation.
abstract: The HERG K+ channel has very unusual kinetic behavior that includes slow activation but rapid inactivation. These features are critical for normal cardiac repolarization as well as in preventing lethal ventricular arrhythmias. Mutagenesis studies have shown that the extracellular peptide linker joining the fifth transmembrane domain to the pore helix is critical for rapid inactivation of the HERG K+ channel. This peptide linker is also considerably longer in HERG K+ channels, 40 amino acids, than in most other voltage-gated K+ channels. In this study we show that a synthetic 42-residue peptide corresponding to this linker region of the HERG K+ channel does not have defined structural elements in aqueous solution; however, it displays two well defined helical regions when in the presence of SDS micelles. The helices correspond to Trp585-Ile593 and Gly604-Tyr611 of the channel. The Trp585-Ile593 helix has distinct hydrophilic and hydrophobic surfaces. The Gly604-Tyr611 helix corresponds to an N-terminal extension of the pore helix. Electrophysiological studies of HERG currents following application of exogenous S5P peptides show that the amphipathic helix in the S5P linker interacts with the pore region of the channel in a voltage-dependent manner.
authors.affiliation: School of Molecular and Microbial Biosciences, University of Sydney, New South Wales 2006, Australia.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Torres
authors.forename: Paramjit S
authors.initials: PS
authors.lastname: Bansal
authors.forename: Margaret
authors.initials: M
authors.lastname: Sunde
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Clarke
authors.forename: Jane A
authors.initials: JA
authors.lastname: Bursill
authors.forename: David J
authors.initials: DJ
authors.lastname: Smith
authors.forename: Asne
authors.initials: A
authors.lastname: Bauskin
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Breit
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Campbell
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kuchel
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
mesh_terms: D000595:Amino Acid Sequence; D027682:Cation Transport Proteins; D002942:Circular Dichroism; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D015221:Potassium Channels / Q000737:chemistry*; D024642:Potassium Channels, Voltage-Gated; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010446:Peptide Fragments; D010455:Peptides; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012967:Sodium Dodecyl Sulfate