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The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel
Max Planck Institute Dynam Complex Technical Syst, Germany.
Max Planck Institute Dynam Complex Technical Syst, Germany.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Science Life Lab, Sweden; KTH, Sweden.
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2016 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, no 1, e1004704- p.Article in journal (Refereed) PublishedText
Abstract [en]

Voltage-gated potassium (K-V) channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs) induce channel opening by modulating the voltage-sensitivity, which can provide effective treatment against refractory epilepsy by means of a ketogenic diet. While PUFAs have been reported to influence the gating mechanism by electrostatic interactions to the voltage-sensor domain (VSD), the exact PUFA-protein interactions are still elusive. In this study, we report on the interactions between the Shaker K-V channel in open and closed states and a PUFA-enriched lipid bilayer using microsecond molecular dynamics simulations. We determined a putative PUFA binding site in the open state of the channel located at the protein-lipid interface in the vicinity of the extracellular halves of the S3 and S4 helices of the VSD. In particular, the lipophilic PUFA tail covered a wide range of non-specific hydrophobic interactions in the hydrophobic central core of the protein-lipid interface, while the carboxylic head group displayed more specific interactions to polar/charged residues at the extracellular regions of the S3 and S4 helices, encompassing the S3-S4 linker. Moreover, by studying the interactions between saturated fatty acids (SFA) and the Shaker K-V channel, our study confirmed an increased conformational flexibility in the polyunsaturated carbon tails compared to saturated carbon chains, which may explain the specificity of PUFA action on channel proteins.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2016. Vol. 12, no 1, e1004704- p.
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-125693DOI: 10.1371/journal.pcbi.1004704ISI: 000369366100033PubMedID: 26751683OAI: diva2:908197

Funding Agencies|Max Planck Society for Advancement of Science; Excellence Initiative "Research Center for Dynamic Systems: Biosystems Engineering"; Swedish Research Council [2013-5901]; Swedish Heart-Lung Foundation; Swedish Brain Foundation; Marie Curie Career Integration Grant [FP7-MC-CIG-618558]; Magnus Bergvalls Stiftelse [2014-00170]; Angstromke Wibergs Stiftelse [M14-0245]; Swedish e-Science Research Center (SeRC)

Available from: 2016-03-01 Created: 2016-02-29 Last updated: 2016-03-29

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