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Volume 11
Journal of Proteomics & Bioinformatics
ISSN: 0974-276X
Structural Biology 2018
September 24-26, 2018
September 24-26, 2018 | Berlin, Germany
14
th
International Conference on
Structural Biology
Cholesterol regulation of Kir channels: Chiral isomers of cholesterol bind to the same site but elicit
differential response
Irena Levitan
and
Nicholas Barbera
University of Illinois at Chicago, USA
N
umerous ion channels have been shown to be regulated by the level of membrane cholesterol but the mechanisms responsible for
these effects are still not well understood. The key question in the field is how to discriminate between the contributions of the two
central mechanisms that might be responsible for the sensitivity of ion channels to cholesterol: specific sterol-protein interactions or
regulation of channels by the bilayer physical properties. Our studies focus on inwardly rectifying K+ (Kir) channels that are ubiquitously
expressed in mammalian cells and are known to play major role in membrane excitability and shear stress sensation. We have shown
that Kir channels are suppressed by loading the cells with cholesterol and enhanced by cholesterol depletion. Comparative analysis of
cholesterol and its isomers on the function of Kir revealed that cholesterol regulates these channels in a stereo-specific manner, suggesting
an involvement of specific sterol–protein interactions. Furthermore, we present new evidence that the stereo specificity of cholesterol–ion
channel interactions may be mediated, not by a lack of binding, has been generally assumed, but by the specificity of the interaction,
which results in a functional effect, in the case of native cholesterol and a lack of functional effect in the case of a cholesterol isomer. In
other words, accumulating evidence suggests that the structural requirements of ion channel cholesterol-binding sites are lax, allowing
chiral isomers of cholesterol to bind to the same site in a non-stereospecific way, but the ability of a sterol to confer a functional effect
on the channel activity can still be stereospecific. This is an important distinction both conceptually and methodologically. Indeed, our
analysis shows that the orientations of cholesterol and its chiral isomer ent-cholesterol within a hydrophobic binding pocket of Kir 2.2 are
significantly different and we propose that this difference may underlie distinct functional outcomes.
J Proteomics Bioinform 2018, Volume 11
DOI: 10.4172/0974-276X-C2-116