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Open Access Publications from the University of California

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

  • Author(s): Arrigoni, C
  • Rohaim, A
  • Shaya, D
  • Findeisen, F
  • Stein, RA
  • Nurva, SR
  • Mishra, S
  • McHaourab, HS
  • Minor, DL
  • et al.

© 2016 Elsevier Inc. Summary 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 (BacNaV) C-terminal cytoplasmic domain (CTD) affects function. Our studies show that the BacNaVCTD 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 BacNaVCTD 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 BacNaVvoltage dependencies, and demonstrate that a discrete domain can encode the temperature-dependent response of a channel.

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