title: Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation.
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.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Arrigoni
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biophysics, Faculty of Science, Cairo University, Giza, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Rohaim
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: David
authors.initials: D
authors.lastname: Shaya
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Findeisen
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stein
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Shailika Reddy
authors.initials: SR
authors.lastname: Nurva
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Smriti
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Hassane S
authors.initials: HS
authors.lastname: Mchaourab
authors.affiliation: 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.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Minor
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D020563:Gammaproteobacteria / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D058767:Protein Unfolding; D016415:Sequence Alignment; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D061566:Voltage-Gated Sodium Channels