Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Gen Physiol
2021 Jun 07;1536:. doi: 10.1085/jgp.202012850.
Show Gene links
Show Anatomy links
Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1.
Yazdi S
,
Nikesjö J
,
Miranda W
,
Corradi V
,
Tieleman DP
,
Noskov SY
,
Larsson HP
,
Liin SI
.
???displayArticle.abstract???
Polyunsaturated fatty acids (PUFAs), but not saturated fatty acids, modulate ion channels such as the cardiac KCNQ1 channel, although the mechanism is not completely understood. Using both simulations and experiments, we find that PUFAs interact directly with the KCNQ1 channel via two different binding sites: one at the voltage sensor and one at the pore. These two amphiphilic binding pockets stabilize the negatively charged PUFA head group by electrostatic interactions with R218, R221, and K316, while the hydrophobic PUFA tail is selectively stabilized by cassettes of hydrophobic residues. The rigid saturated tail of stearic acid prevents close contacts with KCNQ1. By contrast, the mobile tail of PUFA linoleic acid can be accommodated in the crevice of the hydrophobic cassette, a defining feature of PUFA selectivity in KCNQ1. In addition, we identify Y268 as a critical PUFA anchor point underlying fatty acid selectivity. Combined, this study provides molecular models of direct interactions between PUFAs and KCNQ1 and identifies selectivity mechanisms. Long term, this understanding may open new avenues for drug development based on PUFA mechanisms.
???displayArticle.pubmedLink???
33939797
???displayArticle.link???J Gen Physiol ???displayArticle.grants???[+]
Ballweg,
Regulation of lipid saturation without sensing membrane fluidity.
2020, Pubmed
Ballweg,
Regulation of lipid saturation without sensing membrane fluidity.
2020,
Pubmed
Barbera,
Molecular Dynamics Simulations of Kir2.2 Interactions with an Ensemble of Cholesterol Molecules.
2018,
Pubmed
Barhanin,
K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current.
1996,
Pubmed
,
Xenbase
Barrese,
KCNQ-Encoded Potassium Channels as Therapeutic Targets.
2018,
Pubmed
Barro-Soria,
KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps.
2014,
Pubmed
Bavro,
Structure of a KirBac potassium channel with an open bundle crossing indicates a mechanism of channel gating.
2012,
Pubmed
Bohannon,
ω-6 and ω-9 polyunsaturated fatty acids with double bonds near the carboxyl head have the highest affinity and largest effects on the cardiac IKs potassium channel.
2019,
Pubmed
,
Xenbase
Bohannon,
Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms.
2020,
Pubmed
,
Xenbase
Boland,
Polyunsaturated fatty acid modulation of voltage-gated ion channels.
2008,
Pubmed
Broomand,
Large-scale movement within the voltage-sensor paddle of a potassium channel-support for a helical-screw motion.
2008,
Pubmed
,
Xenbase
Börjesson,
Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids.
2008,
Pubmed
,
Xenbase
Cordero-Morales,
Molecular determinants of gating at the potassium-channel selectivity filter.
2006,
Pubmed
Eldho,
Polyunsaturated docosahexaenoic vs docosapentaenoic acid-differences in lipid matrix properties from the loss of one double bond.
2003,
Pubmed
Elinder,
Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels.
2017,
Pubmed
Farag,
Polyunsaturated fatty acids inhibit Kv1.4 by interacting with positively charged extracellular pore residues.
2016,
Pubmed
,
Xenbase
Feller,
Acyl chain conformations in phospholipid bilayers: a comparative study of docosahexaenoic acid and saturated fatty acids.
2008,
Pubmed
Hamilton,
Molecular localization of the inhibitory arachidonic acid binding site to the pore of hIK1.
2003,
Pubmed
Hoshi,
A point mutation in the human Slo1 channel that impairs its sensitivity to omega-3 docosahexaenoic acid.
2013,
Pubmed
Hou,
Inactivation of KCNQ1 potassium channels reveals dynamic coupling between voltage sensing and pore opening.
2017,
Pubmed
,
Xenbase
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Jensen,
Mechanism of voltage gating in potassium channels.
2012,
Pubmed
Jo,
CHARMM-GUI: a web-based graphical user interface for CHARMM.
2008,
Pubmed
Klauda,
Improving the CHARMM force field for polyunsaturated fatty acid chains.
2012,
Pubmed
Kuenze,
Upgraded molecular models of the human KCNQ1 potassium channel.
2019,
Pubmed
Larsson,
KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site.
2018,
Pubmed
,
Xenbase
Lees-Miller,
Interactions of H562 in the S5 helix with T618 and S621 in the pore helix are important determinants of hERG1 potassium channel structure and function.
2009,
Pubmed
Lenaeus,
Structures of closed and open states of a voltage-gated sodium channel.
2017,
Pubmed
Leng,
All n-3 PUFA are not the same: MD simulations reveal differences in membrane organization for EPA, DHA and DPA.
2018,
Pubmed
Liin,
Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations.
2016,
Pubmed
,
Xenbase
Liin,
Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel.
2015,
Pubmed
,
Xenbase
Liin,
Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1.
2018,
Pubmed
,
Xenbase
Lippert,
Accurate and efficient integration for molecular dynamics simulations at constant temperature and pressure.
2013,
Pubmed
Lundbaek,
Lipid bilayer regulation of membrane protein function: gramicidin channels as molecular force probes.
2010,
Pubmed
Marrink,
Computational Modeling of Realistic Cell Membranes.
2019,
Pubmed
Marrink,
The MARTINI force field: coarse grained model for biomolecular simulations.
2007,
Pubmed
Nerbonne,
Molecular physiology of cardiac repolarization.
2005,
Pubmed
Noskov,
Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands.
2004,
Pubmed
Noskov,
Control of ion selectivity in LeuT: two Na+ binding sites with two different mechanisms.
2008,
Pubmed
Oliver,
Functional conversion between A-type and delayed rectifier K+ channels by membrane lipids.
2004,
Pubmed
,
Xenbase
Osteen,
Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels.
2012,
Pubmed
,
Xenbase
Ottosson,
Drug-induced ion channel opening tuned by the voltage sensor charge profile.
2014,
Pubmed
,
Xenbase
Palermo,
Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets.
2015,
Pubmed
Pronk,
GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit.
2013,
Pubmed
Romero,
Dietary fatty acids fine-tune Piezo1 mechanical response.
2019,
Pubmed
Sanguinetti,
Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.
1996,
Pubmed
,
Xenbase
Soubias,
Docosahexaenoyl chains isomerize on the sub-nanosecond time scale.
2007,
Pubmed
Sun,
Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.
2017,
Pubmed
,
Xenbase
Tian,
Atomic determinants of BK channel activation by polyunsaturated fatty acids.
2016,
Pubmed
Westhoff,
IKs ion-channel pore conductance can result from individual voltage sensor movements.
2019,
Pubmed
Xiao,
Single point mutations affect fatty acid block of human myocardial sodium channel alpha subunit Na+ channels.
2001,
Pubmed
Xiao,
The antiarrhythmic effect of n-3 polyunsaturated fatty acids: modulation of cardiac ion channels as a potential mechanism.
2005,
Pubmed
Yazdi,
The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel.
2016,
Pubmed
Zaydman,
Domain-domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel.
2014,
Pubmed
,
Xenbase
de Jong,
Dimerization of Amino Acid Side Chains: Lessons from the Comparison of Different Force Fields.
2012,
Pubmed
de Jong,
Improved Parameters for the Martini Coarse-Grained Protein Force Field.
2013,
Pubmed
