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Evaluating inositol phospholipid interactions with inward rectifier potassium channels and characterising their role in disease

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Pipatpolkai, Tanadet , Corey, Robin A., Proks, Peter , Ashcroft, Frances M. and Stansfeld, Phillip J. (2020) Evaluating inositol phospholipid interactions with inward rectifier potassium channels and characterising their role in disease. Communications chemistry, 3 . 147. doi:10.1038/s42004-020-00391-0

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Official URL: https://doi.org/10.1038/s42004-020-00391-0

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Abstract

Membrane proteins are frequently modulated by specific protein-lipid interactions. The activation of human inward rectifying potassium (hKir) channels by phosphoinositides (PI) has been well characterised. Here, we apply a coarse-grained molecular dynamics free energy perturbation (CG-FEP) protocol to capture the energetics of binding of PI lipids to hKir channels. By using either a single- or multi-step approach, we establish a consistent value for the binding of PIP2 to hKir channels, relative to the binding of the bulk phosphatidylcholine phospholipid. Furthermore, by perturbing amino acid side chains on hKir6.2, we show that the neonatal diabetes mutation E179K increases PIP2 affinity, while the congenital hyperinsulinism mutation K67N results in a reduced affinity. We show good agreement with electrophysiological data where E179K exhibits a reduction in neomycin sensitivity, implying that PIP2 binds more tightly E179K channels. This illustrates the application of CG-FEP to compare affinities between lipid species, and for annotating amino acid residues.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science > Chemistry
Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Membrane proteins, Potassium channels, Inositol, Phospholipids, Molecular dynamics -- Computer simulation
Journal or Publication Title: Communications chemistry
Publisher: Nature Research
ISSN: 2399-3669
Official Date: 30 October 2020
Dates:
DateEvent
30 October 2020Published
17 September 2020Accepted
Date of first compliant deposit: 30 September 2020
Volume: 3
Article Number: 147
DOI: 10.1038/s42004-020-00391-0
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
208361/Z/17/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
MR/S009213/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/P01948X/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/R002517/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/S003339/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
MR/T002107/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/R002517/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/R017220/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
102161/Z/13/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
EP/R029407/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
EP/P020232/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
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