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Phospholipids and the origin of cationic gating charges in voltage sensors

Nature volume 444, pages 775–779 (2006)Cite this article

Abstract

Cells communicate with their external environment through physical and chemical processes that take place in the cell-surrounding membrane. The membrane serves as a barrier as well as a special environment in which membrane proteins are able to carry out important processes. Certain membrane proteins have the ability to detect the membrane voltage and regulate ion conduction or enzyme activity1,2. Such voltage-dependent processes rely on the action of protein domains known as voltage sensors, which are embedded inside the cell membrane and contain an excess of positively charged amino acids, which react to an electric field. How does the membrane create an environment suitable for voltage sensors? Here we show under a variety of conditions that the function of a voltage-dependent K+ channel is dependent on the negatively charged phosphodiester of phospholipid molecules. A non-voltage-dependent K+ channel does not exhibit the same dependence. The data lead us to propose that the phospholipid membrane, by providing stabilizing interactions between positively charged voltage-sensor arginine residues and negatively charged lipid phosphodiester groups, provides an appropriate environment for the energetic stability and operation of the voltage-sensing machinery. We suggest that the usage of arginine residues in voltage sensors is an adaptation to the phospholipid composition of cell membranes.

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Figure 1: Assessment of KvAP and MthK function in phospholipid and DOTAP membranes.
Figure 2: KvAP function depends on membrane lipid composition.
Figure 3: Phosphate group is important for KvAP voltage-dependent gating.
Figure 4: Role of the negative charge on the phosphate group.

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Acknowledgements

We thank Y. Jiang for the MthK channel construct and A. Lee for the CTX. This work was supported by an NIH grant to R.M. R.M. is an investigator in the Howard Hughes Medical Institute.

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Author notes

  1. Daniel Schmidt and Qiu-Xing Jiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute, Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University, New York, 1230 York Avenue, New York, 10021, USA

    Daniel Schmidt, Qiu-Xing Jiang & Roderick MacKinnon

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  1. Daniel Schmidt
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Correspondence to Roderick MacKinnon.

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Supplementary Notes

This file contains the Supplementary Methods and the Supplementary Figures 1 and 2. The Supplementary Methods provide details on the experimental procedures. Supplementary Figure 1 shows a cryo-electron microscopic image of DOGS vesicles with reconstituted KvAP, demonstrating that under our experimental conditions DOGS forms normal bilayers. Supplementary Figure 2 shows KvAP in DOPA vesicles fused into a DOPA bilayer, demonstrating the importance of the phosphate headgroup for voltage-dependent channel function. (DOC 3672 kb)

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Schmidt, D., Jiang, QX. & MacKinnon, R. Phospholipids and the origin of cationic gating charges in voltage sensors. Nature 444, 775–779 (2006). https://doi.org/10.1038/nature05416

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