Identification of Novel Cholesterol-binding Regions in Kir2 Channels

Inwardly rectifying potassium (Kir) channels play an important role in setting the resting membrane potential and modulating membrane excitability. We have recently shown that cholesterol regulates representative members of the Kir family and that in the majority of the cases, cholesterol suppresses...

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Bibliographic Details
Published in:The Journal of biological chemistry 2013-10, Vol.288 (43), p.31154-31164
Main Authors: Rosenhouse-Dantsker, Avia, Noskov, Sergei, Durdagi, Serdar, Logothetis, Diomedes E., Levitan, Irena
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Animals
Cholesterol
Cholesterol - chemistry
Cholesterol - metabolism
Hydrophobic and Hydrophilic Interactions
Ion Channels
Kir Channels
Lipids
Membrane Biology
Membrane Lipids
Molecular Docking Simulation
Oocytes
Potassium Channels
Potassium Channels, Inwardly Rectifying - chemistry
Potassium Channels, Inwardly Rectifying - genetics
Potassium Channels, Inwardly Rectifying - metabolism
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Xenopus laevis
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Summary:Inwardly rectifying potassium (Kir) channels play an important role in setting the resting membrane potential and modulating membrane excitability. We have recently shown that cholesterol regulates representative members of the Kir family and that in the majority of the cases, cholesterol suppresses channel function. Furthermore, recent data indicate that cholesterol regulates Kir channels by specific sterol-protein interactions, yet the location of the cholesterol binding site in Kir channels is unknown. Using a combined computational-experimental approach, we show that cholesterol may bind to two nonanular hydrophobic regions in the transmembrane domain of Kir2.1 located between adjacent subunits of the channel. The location of the binding regions suggests that cholesterol modulates channel function by affecting the hinging motion at the center of the pore-lining transmembrane helix that underlies channel gating either directly or through the interface between the N and C termini of the channel. Background: Cholesterol modulates inwardly rectifying potassium (Kir) channels. Results: Using a combined computational-experimental approach, we identified two putative cholesterol-binding regions in Kir2.1 that suggest the existence of a novel cholesterol binding motif. Conclusion: Cholesterol binds to nonannular surfaces in the transmembrane domain of Kir2.1. Significance: These findings provide new insights into the mechanisms underlying lipid regulation of ion channels.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.496117