Electromechanical coupling in the hyperpolarization-activated K+ channel KAT1

Article

关键词: CRYO-EM STRUCTURE;    VOLTAGE SENSOR;    MOLECULAR-DYNAMICS;    ION CHANNELS;    STRUCTURAL BASIS;    GATING CHARGE;    PORE DOMAIN;    MODEL;    TOOLS;    VISUALIZATION;   

DOI  :  10.1038/s41586-020-2335-4

来源: SCIE

【 摘 要 】

Voltage-gated potassium (K-v) channels coordinate electrical signalling and control cell volume by gating in response to membrane depolarization or hyperpolarization. However, although voltage-sensing domains transduce transmembrane electric field changes by a common mechanism involving the outward or inward translocation of gating charges(1-3), the general determinants of channel gating polarity remain poorly understood(4). Here we suggest a molecular mechanism for electromechanical coupling and gating polarity in non-domain-swapped K-v channels on the basis of the cryo-electron microscopy structure of KAT1, the hyperpolarization-activated K-v channel from Arabidopsis thaliana. KAT1 displays a depolarized 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 the C-linker hairpin in the adjacent pore subunit is the primary determinant of gating polarity. We suggest that an inward motion of the S4 sensor helix of approximately 5-7 angstrom can underlie 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 cyclic nucleotide-gated channels(5), and may represent an unexpected link between depolarization- and hyperpolarization-activated channels. The cryo-electron microscopy structure of the hyperpolarization-activated K+ channel KAT1 points to a direct-coupling mechanism between S4 movement and the reorientation of the C-linker.

【 授权许可】

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