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Volume 10, Issue 8 (Suppl) J Proteomics Bioinform, an open access journal
ISSN: 0974-276X Structural Biology 2017
September 18-20, 2017
9th International Conference on
Structural Biology
September 18-20, 2017 Zurich, Switzerland
Irena Levitan, J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0100
Structural insights into cholesterol regulation of inwardly-rectifying K+ channels
Irena Levitan
University of Illinois, USA
Cholesterol is known to play a significant role in regulating the function of multiple membrane proteins including a growing
number of ion channels. Our studies focus on inwardly-rectifying K+ (Kir) channels that are ubiquitously expressed
in mammalian cells and are known to play key role in membrane excitability and shear stress sensation. In this study, we
have shown that Kir channels are suppressed by loading the cells with cholesterol and enhanced by cholesterol depletion. A
series of studies revealed that cholesterol interacts with the channels directly by stabilizing them in a long-lived closed “silent”
state and that multiple structural features of the channels are essential for conferring their cholesterol sensitivity. Using a
combined computational-experimental approach, we show that cholesterol may bind to two non-annular regions that form
hydrophobic pockets between the transmembrane helices of the adjacent subunits of the channel. The location of the binding
regions suggests that, cholesterol modulates channel function by affecting the hinging motion at the centre of the pore-lining
transmembrane helix that underlies channel gating. In addition, we identified a series of residues in the C and N-terminus of
the channel. These are critical for conferring cholesterol sensitivity to the channels, but are not part of the binding sites. These
residues form a distinct cytosolic structure, a cholesterol sensitivity belt which surrounds the cytosolic pore of the channel in
proximity to the transmembrane (TM) domain, and includes residues whose mutation results in abrogation of the channel’s
cholesterol sensitivity. Further analysis identified a reversal residue chain comprised of residues that link one of the cholesterol
sensitivity belt residues with a distant cytosolic residue that constitute a two-way molecular switch of the channel sensitivity to
cholesterol. Further studies are needed to elucidate the connection between cholesterol binding and channel.
Biography
Irena Levitan has completed her PhD and is a Professor of Medicine and Adjunct Professor of Bioengineering at the University of Illinois at Chicago. Her current
research focuses on cholesterol regulation of ion channels and cellular biomechanics. Her group has provided the first comprehensive structural insights into
cholesterol regulation of K+ channels and the cross-talk between cholesterol and other regulators of these channels. She was named a Guyton Distinguished
Lecturer by the Association Chairs of Departments of Physiology for her quantitative and biophysical work on cholesterol modulation of ion channels and how this
can affect integrated organ function. She is an author of more than 70 publications and a leading Editor of Cholesterol Regulation of Ion Channels and Receptors
(Wiley, 2012) and Vascular Ion Channels in Physiology and Disease (Springer, 2016).