Structural basis of voltage-dependent gating in BK channels

Gustavo F. Contreras, Rong Shen, Ramon Latorre and Eduardo Perozo ()
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Gustavo F. Contreras: The University of Chicago
Rong Shen: The University of Chicago
Ramon Latorre: Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valparaíso
Eduardo Perozo: The University of Chicago

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The allosteric communication between the pore domain, voltage sensors, and Ca2+ binding sites in the calcium- and voltage-activated K+ channel (BK) underlies its physiological role as the preeminent signal integrator in excitable systems. BK displays shallow voltage sensitivity with very fast gating charge kinetics, yet little is known about the molecular underpinnings of this distinctive behavior. Here, we explore the mechanistic basis of coupling between voltage-sensing domains (VSDs) and calcium sensors in Aplysia BK by locking the VSDs in their activated (R196Q and R199Q) and resting (R202Q) states, with or without calcium. Cryo-EM structures of these mutants reveal unique tilts at the S4 C-terminal end, together with large side-chain rotameric excursions of the gating charges. Notably, the VSD resting structure (R202Q) also revealed BK in its elusive, fully closed state, highlighting the reciprocal relation between calcium and voltage sensors. These structures provide a plausible path where voltage and Ca2+ binding couple energetically and define the conformation of the pore domain and, thus, BK’s full functional range.

Date: 2025
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DOI: 10.1038/s41467-025-60639-y

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