title: Closing in on the resting state of the Shaker K(+) channel.
abstract: Membrane depolarization causes voltage-gated ion channels to transition from a resting/closed conformation to an activated/open conformation. We used voltage-clamp fluorometry to measure protein motion at specific regions of the Shaker Kv channel. This enabled us to construct new structural models of the resting/closed and activated/open states based on the Kv1.2 crystal structure using the Rosetta-Membrane method and molecular dynamics simulations. Our models account for the measured gating charge displacement and suggest a molecular mechanism of activation in which the primary voltage sensors, S4s, rotate by approximately 180 degrees as they move "outward" by 6-8 A. A subsequent tilting motion of the S4s and the pore domain helices, S5s, of all four subunits induces a concerted movement of the channel's S4-S5 linkers and S6 helices, allowing ion conduction. Our models are compatible with a wide body of data and resolve apparent contradictions that previously led to several distinct models of voltage sensing.
authors.affiliation: Biophysics Graduate Program, University of California Berkeley, Berkeley, CA 94720, USA.
authors.forename: Medha M
authors.initials: MM
authors.lastname: Pathak
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.forename: Gautam
authors.initials: G
authors.lastname: Agarwal
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
authors.forename: Patrick
authors.initials: P
authors.lastname: Barth
authors.forename: Susy
authors.initials: S
authors.lastname: Kohout
authors.forename: Francesco
authors.initials: F
authors.lastname: Tombola
authors.forename: Ehud Y
authors.initials: EY
authors.lastname: Isacoff
mesh_terms: D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology* / Q000528:radiation effects; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051637:Shaker Superfamily of Potassium Channels / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D051637:Shaker Superfamily of Potassium Channels