Key result
Cbv1 cytosolic C tail domains mediate BK channel cholesterol sensitivity via specific CRAC motifs.
This study identifies multiple CRAC motifs in the cytosolic C tail of the Slo1 subunit that determine the unique cholesterol sensitivity of BK channels.
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May guide BK channel modulator design; leaves open human cardiovascular translation from animal data.
Large conductance, Ca(2+)- and voltage-gated K(+) (BK) channel proteins are ubiquitously expressed in cell membranes and control a wide variety of biological processes. Membrane cholesterol regulates the activity of membrane-associated proteins, including BK channels. Cholesterol modulation of BK channels alters action potential firing, colonic ion transport, smooth muscle contractility, endothelial function, and the channel alcohol response. The structural bases underlying cholesterol-BK channel interaction are unknown. Such interaction is determined by strict chemical requirements for the sterol molecule, suggesting cholesterol recognition by a protein surface. Here, we demonstrate that cholesterol action on BK channel-forming Cbv1 proteins is mediated by their cytosolic C tail domain, where we identified seven cholesterol recognition/interaction amino acid consensus motifs (CRAC4 to 10), a distinct feature of BK proteins. Cholesterol sensitivity is provided by the membrane-adjacent CRAC4, where Val-444, Tyr-450, and Lys-453 are required for cholesterol sensing, with hydrogen bonding and hydrophobic interactions participating in cholesterol location and recognition. However, cumulative truncations or Tyr-to-Phe substitutions in CRAC5 to 10 progressively blunt cholesterol sensitivity, documenting involvement of multiple CRACs in cholesterol-BK channel interaction. In conclusion, our study provides for the first time the structural bases of BK channel cholesterol sensitivity; the presence of membrane-adjacent CRAC4 and the long cytosolic C tail domain with several other CRAC motifs, which are not found in other members of the TM6 superfamily of ion channels, very likely explains the unique cholesterol sensitivity of BK channels.
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Singh et al. (2012) studied this question. Cholesterol and CRAC motif mutations was evaluated on Cholesterol sensitivity. Cholesterol sensitivity of BK channels is mediated by the cytosolic C tail domain of Cbv1 proteins, specifically requiring the membrane-adjacent CRAC4 motif and multiple other CRAC motifs.
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