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Cell. 2016 Feb 25;164(5):922-36. doi: 10.1016/j.cell.2016.02.001.

Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation.

Author information

1
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biophysics, Faculty of Science, Cairo University, Giza, Egypt.
3
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
4
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94158, USA; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: daniel.minor@ucsf.edu.

Abstract

Voltage-gated ion channels (VGICs) are outfitted with diverse cytoplasmic domains that impact function. To examine how such elements may affect VGIC behavior, we addressed how the bacterial voltage-gated sodium channel (BacNa(V)) C-terminal cytoplasmic domain (CTD) affects function. Our studies show that the BacNa(V) CTD exerts a profound influence on gating through a temperature-dependent unfolding transition in a discrete cytoplasmic domain, the neck domain, proximal to the pore. Structural and functional studies establish that the BacNa(V) CTD comprises a bi-partite four-helix bundle that bears an unusual hydrophilic core whose integrity is central to the unfolding mechanism and that couples directly to the channel activation gate. Together, our findings define a general principle for how the widespread four-helix bundle cytoplasmic domain architecture can control VGIC responses, uncover a mechanism underlying the diverse BacNa(V) voltage dependencies, and demonstrate that a discrete domain can encode the temperature-dependent response of a channel.

PMID:
26919429
PMCID:
PMC4769381
[Available on 2017-02-25]
DOI:
10.1016/j.cell.2016.02.001
[Indexed for MEDLINE]
Free PMC Article
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