title: Two separate interfaces between the voltage sensor and pore are required for the function of voltage-dependent K(+) channels.
abstract: Voltage-dependent K(+) (Kv) channels gate open in response to the membrane voltage. To further our understanding of how cell membrane voltage regulates the opening of a Kv channel, we have studied the protein interfaces that attach the voltage-sensor domains to the pore. In the crystal structure, three physical interfaces exist. Only two of these consist of amino acids that are co-evolved across the interface between voltage sensor and pore according to statistical coupling analysis of 360 Kv channel sequences. A first co-evolved interface is formed by the S4-S5 linkers (one from each of four voltage sensors), which form a cuff surrounding the S6-lined pore opening at the intracellular surface. The crystal structure and published mutational studies support the hypothesis that the S4-S5 linkers convert voltage-sensor motions directly into gate opening and closing. A second co-evolved interface forms a small contact surface between S1 of the voltage sensor and the pore helix near the extracellular surface. We demonstrate through mutagenesis that this interface is necessary for the function and/or structure of two different Kv channels. This second interface is well positioned to act as a second anchor point between the voltage sensor and the pore, thus allowing efficient transmission of conformational changes to the pore's gate.
authors.affiliation: Howard Hughes Medical Institute, Rockefeller University, New York, NY, USA.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.forename: Roderick
authors.initials: R
authors.lastname: MacKinnon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000502:physiology*; D004220:Disulfides; D004594:Electrophysiology; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D018272:Porins / Q000737:chemistry / Q000502:physiology*; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000502:physiology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000502:physiology
chemical_list: D004220:Disulfides; D018272:Porins; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium