Lipid-mediated hydrophobic gating in the BK potassium channel

Lucia Coronel, Giovanni Muccio (), Brad S. Rothberg, Alberto Giacomello and Vincenzo Carnevale ()
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Lucia Coronel: Temple University
Giovanni Muccio: Sapienza University of Rome
Brad S. Rothberg: Temple University Lewis Katz School of Medicine
Alberto Giacomello: Sapienza University of Rome
Vincenzo Carnevale: Temple University

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Structures of the large-conductance, calcium-activated potassium (BK) channel in the Ca2+ −bound and Ca2+ −free states have suggested that K+ conduction is not gated via a steric closure of the pore-lining helices of the channel, in contrast to the gating mechanism of other 6TM channels. This has raised the question of how gating might occur in the absence of apparent steric hindrance by protein residues. To answer this question, we perform molecular simulations and free-energy calculations to develop a microscopic picture of the gating mechanism. Our results highlight an unexpected role for annular lipids, which appear to be an integral part of the gating machinery. In the Ca2+ −free (“closed”) pore, methyl groups from lipid alkyl chains can enter the pore through fenestrations between the pore-lining helices. This dynamic occupancy directly contributes to dewetting of the inner-pore cavity, thus hindering ion conduction. In contrast, Ca2+ binding leads to occlusion of the fenestrations, thus preventing the lipids from entering the pore cavity and permitting pore hydration and ion conduction. This apparent lipid-mediated hydrophobic gating may also explain functional observations that include state-dependent pore accessibility of hydrophobic channel blockers.

Date: 2025
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DOI: 10.1038/s41467-025-61638-9

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