TY - JOUR
T1 - Identification of pufa interaction sites on the cardiac potassium channel kcnq1
AU - Yazdi, Samira
AU - Nikesjö, Johan
AU - Miranda, Williams
AU - Corradi, Valentina
AU - Peter Tieleman, D.
AU - Noskov, Sergei Yu
AU - Peter Larsson, H.
AU - Liin, Sara I.
N1 - Funding Information:
Computational resources were provided by the Swedish National Infrastructure for Computing (2017/1-290; 2018/3-316). Anton2 computer time was provided by the Pittsburgh Supercomputing Center through a grant from the National Institutes of Health (R01GM116961). The Anton2 machine at the Pittsburgh Supercomputing Center was generously made available by D.E. Shaw Research. The computational support for this work was partially provided by Compute Canada through a resource allocation award to S.Yu. Noskov and D.P. Tieleman. This work was supported by the Swedish Society for Medical Research (to S.I. Liin), the Swedish Research Council (2017-02040, to S.I. Liin), the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 850622), and the National Institutes of Health (R01HL131461, to H.P. Larsson). S. Yazdi was supported by the Center for Systems Neurobiology at Linköping University. The work in Calgary was supported by the Canadian Institutes of Health Research Project Grant FRN-CIHR: 156236 (D.P. Tieleman and S.Yu. Noskov) and Discovery grants from the Natural Scientific and Engineering Research Council of Canada (to D.P. Tieleman and S.Yu. Noskov). Further support came from the Canada Research Chairs program (D.P. Tieleman). W. Miranda would like to acknowledge support from a Vanier Canada Graduate scholarship, a Killam scholarship, and an Alberta Innovates Health Solutions studentship.
Funding Information:
Jeanne M. Nerbonne served as editor. Computational resources were provided by the Swedish National Infrastructure for Computing (2017/1-290; 2018/3-316). Anton2 computer time was provided by the Pittsburgh Super-computing Center through a grant from the National Institutes of Health (R01GM116961). The Anton2 machine at the Pittsburgh Supercomputing Center was generously made available by D.E. Shaw Research. The computational support for this work was partially provided by Compute Canada through a resource allo-cation award to S.Yu. Noskov and D.P. Tieleman. This work was supported by the Swedish Society for Medical Research (to S.I. Liin), the Swedish Research Council (2017-02040, to S.I. Liin), the European Research Council under the European Union?s Horizon 2020 research and innovation program (grant agree-ment no. 850622), and the National Institutes of Health (R01HL131461, to H.P. Larsson). S. Yazdi was supported by the Center for Systems Neurobiology at Link?ping University. The work in Calgary was supported by the Canadian Institutes of Health Research Project Grant FRN-CIHR: 156236 (D.P. Tieleman and S.Yu. Noskov) and Discovery grants from the Natural Scientific and Engineering Research Council of Canada (to D.P. Tieleman and S.Yu. Noskov). Further support came from the Canada Research Chairs program (D.P. Tieleman). W. Miranda would like to acknowledge support from a Vanier Canada Graduate scholarship, a Killam scholarship, and an Alberta In-novates Health Solutions studentship. A patent application (#62/032,739), including a description of the interaction of charged lipophilic compounds with the KCNQ1 channel, has been submitted by the University of Miami with H.P. Larsson and S.I. Liin identified as inventors. The remaining authors declare no competing financial interests. Author contributions: S. Yazdi, W. Miranda, V. Corradi, D.P. Tieleman, S.Yu. Noskov, H.P. Larsson, and S.I. Liin contributed to study design and analysis approaches. S. Yazdi performed computational simulations. J. Nikesj? and S.I. Liin performed electrophysiological experiments. All authors commented on the manuscript and approved the final version.
Publisher Copyright:
© 2021 Yazdi et al.
PY - 2021/6/7
Y1 - 2021/6/7
N2 - 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.
AB - 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.
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U2 - 10.1085/jgp.202012850
DO - 10.1085/jgp.202012850
M3 - Article
C2 - 33939797
AN - SCOPUS:85105359519
VL - 153
JO - Journal of General Physiology
JF - Journal of General Physiology
SN - 0022-1295
IS - 6
M1 - e202012850
ER -