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Portability of paddle motif function and pharmacology in voltage sensors

Nature volume 450, pages 370–375 (2007)Cite this article

Abstract

Voltage-sensing domains enable membrane proteins to sense and react to changes in membrane voltage. Although identifiable S1–S4 voltage-sensing domains are found in an array of conventional ion channels and in other membrane proteins that lack pore domains, the extent to which their voltage-sensing mechanisms are conserved is unknown. Here we show that the voltage-sensor paddle, a motif composed of S3b and S4 helices, can drive channel opening with membrane depolarization when transplanted from an archaebacterial voltage-activated potassium channel (KvAP) or voltage-sensing domain proteins (Hv1 and Ci-VSP) into eukaryotic voltage-activated potassium channels. Tarantula toxins that partition into membranes can interact with these paddle motifs at the protein–lipid interface and similarly perturb voltage-sensor activation in both ion channels and proteins with a voltage-sensing domain. Our results show that paddle motifs are modular, that their functions are conserved in voltage sensors, and that they move in the relatively unconstrained environment of the lipid membrane. The widespread targeting of voltage-sensor paddles by toxins demonstrates that this modular structural motif is an important pharmacological target.

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Figure 1: Transfer of the voltage-sensor paddle motif from KvAP to Kv2.1 channels.
Figure 2: Sensitivity of KvAP paddle chimaeras to extracellular tarantula toxins.
Figure 3: Structural analysis of the toxin–paddle interaction.
Figure 4: Transfer of the voltage-sensor paddle motif from Hv1 or Ci-VSP into Kv2.1 channels.
Figure 5: Sensitivity of a Hv1 paddle chimaera and the Hv1 proton channel to tarantula toxins.
Figure 6: Tarantula toxins interacting with voltage-sensor paddle motifs.

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Acknowledgements

We thank F. Fontaine, M. Mayer, J. Mindell, S. Ramsey, S. Silberberg and members of the Swartz laboratory for discussions, and the NINDS DNA sequencing facility for DNA sequencing. We thank T. Kitaguchi for cloning KvAP and Y. Okamura for providing Ci-VSP complementary DNA. This work was supported by the Intramural Research Program of the NINDS, NIH. A.A.A. was partially supported by the NIH Undergraduate Scholarship Program.

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  1. AbdulRasheed A. Alabi and Maria Isabel Bahamonde: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA ,

    AbdulRasheed A. Alabi, Maria Isabel Bahamonde & Kenton J. Swartz

  2. Department of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 500-712, Korea,

    Hoi Jong Jung & Jae Il Kim

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Correspondence to Kenton J. Swartz.

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Alabi, A., Bahamonde, M., Jung, H. et al. Portability of paddle motif function and pharmacology in voltage sensors. Nature 450, 370–375 (2007). https://doi.org/10.1038/nature06266

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