title: The twisted ion-permeation pathway of a resting voltage-sensing domain.
abstract: Proteins containing voltage-sensing domains (VSDs) translate changes in membrane potential into changes in ion permeability or enzymatic activity. In channels, voltage change triggers a switch in conformation of the VSD, which drives gating in a separate pore domain, or, in channels lacking a pore domain, directly gates an ion pathway within the VSD. Neither mechanism is well understood. In the Shaker potassium channel, mutation of the first arginine residue of the S4 helix to a smaller uncharged residue makes the VSD permeable to ions ('omega current') in the resting conformation ('S4 down'). Here we perform a structure-guided perturbation analysis of the omega conductance to map its VSD permeation pathway. We find that there are four omega pores per channel, which is consistent with one conduction path per VSD. Permeating ions from the extracellular medium enter the VSD at its peripheral junction with the pore domain, and then plunge into the core of the VSD in a curved conduction pathway. Our results provide a model of the resting conformation of the VSD.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tombola
authors.forename: Medha M
authors.initials: MM
authors.lastname: Pathak
authors.forename: Pau
authors.initials: P
authors.lastname: Gorostiza
authors.forename: Ehud Y
authors.initials: EY
authors.lastname: Isacoff
mesh_terms: D000818:Animals; D004553:Electric Conductivity; D015640:Ion Channel Gating; D017136:Ion Transport; D008958:Models, Molecular; D009865:Oocytes / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D051637:Shaker Superfamily of Potassium Channels; D011188:Potassium