Abstract
ABSTRACTCholesterol is a major component of the membrane and a key regulator of many ion channels. Multiple studies showed that cholesterol regulates ion channels in a stereospecific manner, with cholesterol but not its chiral isomers having a functional effect. This stereospecificity has been universally attributed to the specificity of cholesterol binding, with the assumption that only native cholesterol binds to the channels whereas its isomers do not. In this study, we challenge this paradigm by docking analyses of cholesterol and its chiral isomers to five ion channels whose response to cholesterol was shown to be stereospecific, Kir2.2, KirBac1.1, TRPV1, GABAA and BK. The analysis is performed using AutoDock Vina to predict the binding poses and energies of the sterols to the channels and identify amino acids interacting with the sterol molecules. We found that for every ion channel tested herein all three sterols showed similar binding poses and significant overlap in the set of the amino acids that comprise the predicted binding sites, along with similar energetic favorability to these overlapping sites. We also found, however, that specific orientations of the three sterols within the binding sites of the channels are distinct, so that a subset of the interacting amino acids is unique to each sterol. We propose therefore, that contrary to previous thought, stereospecific effects of cholesterol should be attributed not to the lack of binding of the stereoisomers but to specific, unique interactions between the cholesterol molecule and the residues within the binding sites of the channels.
Highlights
Cholesterol is an integral component of cell membranes, comprising anywhere from 10 to 45% of the lipid bilayer of mammalian cells [1]
We found for Kir2.2 that the predicted binding sites for cholesterol, epicholesterol, and ent-cholesterol showed a high degree of overlap
The top scoring poses for cholesterol, epicholesterol, and ent-cholesterol were compared, and to what we found in Kir channels, here we find that all three isomers are predicted to bind to the channel in a similar location
Summary
Cholesterol is an integral component of cell membranes, comprising anywhere from 10 to 45% of the lipid bilayer of mammalian cells [1]. In addition to playing an important role in controlling membrane fluidity and altering lipid packing [1,2], cholesterol has been shown to be an important regulator for a wide array of membraneembedded proteins, including ion channels. For many of these channels, in particular K+ channels, cholesterol has an inhibitory effect on the channel activity. Inwardly rectifying K+ channels [3,4], Ca2+-sensitive K+ channels [5,6], and voltage-gated K+ channels [7,8] are all suppressed by the elevation of membrane cholesterol level. Cholesterol has been shown to be necessary for the activity of nicotinic acetylcholine receptors, and is thought to stabilize them in the open state [11,12,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
