1. Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA
2. Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
3. Present addresses: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA (M.M.P.); Center of Bioengineering of Catalonia (CREBEC), 08028 Barcelona, Spain (P.G).

Correspondence to: Ehud Y. Isacoff^1,2 Correspondence and requests for materials should be addressed to E.I. (Email: ehud@berkeley.edu).

Abstract

Proteins containing voltage-sensing domains (VSDs) translate changes in membrane potential into changes in ion permeability or enzymatic activity^{1, 2, 3}. 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^{4, 5}. Neither mechanism is well understood⁶. 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')⁷. 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.

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