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Abstract

Voltage-gated potassium (Kv) channels orchestrate electrical signaling and control cell volume by gating in response to either membrane depolarization or hyperpolarization. Yet, while all voltage-sensing domains transduce transmembrane electric fields by a common mechanism involving the outward translocation of gating charges (Bezanilla 2008, Mannikko et al. 2002, Latorre et al. 2003), the general determinants of gating polarity remain poorly understood (Blunck and Batulan 2012). Here, we provide a molecular mechanism for electromechanical coupling and gating polarity in non-domain-swapped Kv channels based on the cryo-EM structure of KAT1, the hyperpolarization-activated Kv channel from Arabidopsis thaliana. KAT1 displays an activated voltage sensor, which interacts with a closed pore domain directly via two interfaces and indirectly via an intercalated phospholipid. Functional evaluation of KAT1 structure-guided mutants at the sensor-pore interfaces suggests a mechanism in which direct interaction between the sensor and C-linker hairpin in the adjacent pore subunit is the primary determinant of gating polarity. We suggest that a ~5-7 Å inward motion of the S4 sensor helix underlies a direct-coupling mechanism, driving a conformational reorientation of the C-linker and ultimately opening the activation gate formed by the S6 intracellular bundle. This direct-coupling mechanism contrasts with allosteric mechanisms proposed for hyperpolarization-activated HCN channels (Altomare et al. 2001), and represents an unexpected link between depolarization and hyperpolarization-activated channels.

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