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The twisted ion-permeation pathway of a resting voltage-sensing domain

Nature volume 445, pages 546–549 (2007)Cite this article

Abstract

Proteins containing voltage-sensing domains (VSDs) translate changes in membrane potential into changes in ion permeability or enzymatic activity1,2,3. 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 VSD4,5. 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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Figure 1: Perturbation of omega current by mutation and MTS modification.
Figure 2: Alpha and omega pores in the BOM channel.
Figure 3: Impact of side-chain manipulations on omega current amplitude.
Figure 4: The omega pathway in the resting VSD.

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Acknowledgements

We thank S. Wiese for valuable technical assistance, S. Chakravarthy for help with PyMOL, H. P. Larsson for advice about fluctuation analysis, V. Yarov-Yarovoy for the PDB coordinates of the ROSETTA model of KV1.2 and for helpful discussion, and S. Kohout and S. Bell for critical comments on the manuscripts. This work was supported by the National Institutes of Health and by a postdoctoral fellowship from the American Heart Association Western States Affiliate (F.T.). P.G. was supported by postdoctoral fellowships from the Generalitat de Catalunya and the Human Frontier Science Program.

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Author notes

  1. Medha M. Pathak

    Present address: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, 02115, USA

  2. Pau Gorostiza

    Present address: Center of Bioengineering of Catalonia (CREBEC), 08028, Barcelona, Spain

Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California, California, 94720, Berkeley, USA

    Francesco Tombola, Medha M. Pathak, Pau Gorostiza & Ehud Y. Isacoff

  2. Physical Bioscience Division, Lawrence Berkeley National Laboratory, California, 94720, Berkeley, USA

    Ehud Y. Isacoff

Authors
  1. Francesco Tombola
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  4. Ehud Y. Isacoff
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Correspondence to Ehud Y. Isacoff.

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Tombola, F., Pathak, M., Gorostiza, P. et al. The twisted ion-permeation pathway of a resting voltage-sensing domain. Nature 445, 546–549 (2007). https://doi.org/10.1038/nature05396

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