A gating lever and molecular logic gate that couple voltage and calcium sensor activation to opening in BK potassium channels.

ABSTRACT: BK channels uniquely integrate voltage and calcium signaling in diverse cell types through allosteric activation of their K⁺-conducting pore by structurally distinct V and Ca²⁺ sensor domains. Here, we define mechanisms and interaction pathways that link V sensors to the pore by analyzing effects on allosteric coupling of point mutations in the context of Slo1 BK channel structure. A gating lever, mediated by S4/S5 segment interaction within the transmembrane domain, rotates to engage and stabilize the open conformation of the S6 inner pore helix upon V sensor activation. In addition, an indirect pathway, mediated by the carboxyl-terminal cytosolic domain (CTD) and C-linker that connects the CTD to S6, stabilizes the closed conformation when V sensors are at rest. Unexpectedly, this mechanism, which bypasses the covalent connections of C-linker to CTD and pore, also transduces Ca²⁺-dependent coupling in a manner that is completely nonadditive with voltage, analogous to the function of a digital logic (OR) gate.

SUBMITTER: Sun L 

PROVIDER: S-EPMC9750137 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature