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


Arrigoni CCristina , Rohaim A Ahmed , Shaya D David , Findeisen F Felix , Stein RA Richard A , Nurva SR Shailika Reddy , Mishra S Smriti , Mchaourab HS Hassane S , Minor DL Daniel L . Cell. 2016 2 25; 164(5). 922-36


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 BacNaV 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 BacNaV 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 BacNaV voltage dependencies, and demonstrate that a discrete domain can encode the temperature-dependent response of a channel.