Ball-and-chain inactivation of a human large conductance calcium-activated potassium channel

Shubhangi Agarwal, Elizabeth D. Kim, Sangyun Lee, Alexander Simon, Alessio Accardi and Crina M. Nimigean ()
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Shubhangi Agarwal: Weill Cornell Medical College
Elizabeth D. Kim: Weill Cornell Medical College
Sangyun Lee: Weill Cornell Medical College
Alexander Simon: Weill Cornell Medical College
Alessio Accardi: Weill Cornell Medical College
Crina M. Nimigean: Weill Cornell Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract BK channels are large-conductance calcium (Ca2+)-activated potassium channels crucial for neuronal excitability, muscle contraction, and neurotransmitter release. The pore-forming (α) subunits co-assemble with auxiliary (β and γ) subunits that modulate their function. Previous studies demonstrated that the N-termini of β2-subunits can inactivate BK channels, but with no structural correlate. Here, we investigate BK β2-subunit inactivation using cryo-electron microscopy, electrophysiology and molecular dynamics simulations. We find that the β2 N-terminus occludes the pore only in the Ca2+-bound open state, via a ball-and-chain mechanism. The first three hydrophobic residues of β2 are crucial for occlusion, while the remainder of the N-terminus remains flexible. Neither the closed channel conformation obtained in the absence of Ca2+ nor an intermediate conformation found in the presence of Ca2+ show density for the N-terminus of the β2 subunit in their pore, likely due to narrower side access portals preventing their entry into the channel pore.

Date: 2025
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DOI: 10.1038/s41467-025-56844-4

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