The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel

被引:48
作者
Yazdi, Samira [1 ]
Stein, Matthias [1 ]
Elinder, Fredrik [2 ]
Andersson, Magnus [3 ,4 ]
Lindahl, Erik [3 ,4 ,5 ]
机构
[1] Max Planck Inst Dynam Complex Tech Syst, Mol Simulat & Design Grp, Magdeburg, Germany
[2] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden
[3] Sci Life Lab, Stockholm, Sweden
[4] KTH, Royal Inst Technol, Dept Theoret Phys, Theoret & Computat Biophys, Stockholm, Sweden
[5] Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res, S-10691 Stockholm, Sweden
基金
瑞典研究理事会;
关键词
LINEAR CONSTRAINT SOLVER; K+ CHANNEL; KETOGENIC DIET; DOCOSAHEXAENOIC-ACID; CALCIUM-CHANNELS; SODIUM CURRENTS; LIPID-BILAYERS; NA+ CHANNELS; ION CHANNELS; SENSOR;
D O I
10.1371/journal.pcbi.1004704
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页数:19
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