title: Tracking a complete voltage-sensor cycle with metal-ion bridges.
abstract: Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 Å along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Henrion
authors.forename: Jakob
authors.initials: J
authors.lastname: Renhorn
authors.forename: Sara I
authors.initials: SI
authors.lastname: Börjesson
authors.forename: Erin M
authors.initials: EM
authors.lastname: Nelson
authors.forename: Christine S
authors.initials: CS
authors.lastname: Schwaiger
authors.forename: Pär
authors.initials: P
authors.lastname: Bjelkmar
authors.forename: Björn
authors.initials: B
authors.lastname: Wallner
authors.forename: Erik
authors.initials: E
authors.lastname: Lindahl
authors.forename: Fredrik
authors.initials: F
authors.lastname: Elinder
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002104:Cadmium / Q000737:chemistry / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D003198:Computer Simulation; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008670:Metals / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D002614:Chelating Agents; D029721:Drosophila Proteins; D008670:Metals; C496929:Sh protein, Drosophila; D051637:Shaker Superfamily of Potassium Channels; D002104:Cadmium; D004533:Egtazic Acid