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Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes

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Yamamoto, Eiji, Domański,, Jan, Naughton, Fiona B., Best , Robert B., Kalli, Antreas C., Stansfeld, Phillip J. and Sansom, Mark S. P. (2020) Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes. Science Advances, 6 (8). eaay5736. doi:10.1126/sciadv.aay5736

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Official URL: http://dx.doi.org/10.1126/sciadv.aay5736

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Abstract

Association of peripheral proteins with lipid bilayers regulates membrane signaling and dynamics. Pleckstrin homology (PH) domains bind to phosphatidylinositol phosphate (PIP) molecules in membranes. The effects of local PIP enrichment on the interaction of PH domains with membranes is unclear. Molecular dynamics simulations allow estimation of the binding energy of GRP1 PH domain to PIP3-containing membranes. The free energy of interaction of the PH domain with more than two PIP3 molecules is comparable to experimental values, suggesting that PH domain binding involves local clustering of PIP molecules within membranes. We describe a mechanism of PH binding proceeding via an encounter state to two bound states which differ in the orientation of the protein relative to the membrane, these orientations depending on the local PIP concentration. These results suggest that nanoscale clustering of PIP molecules can control the strength and orientation of PH domain interaction in a concentration-dependent manner.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Bilayer lipid membranes, Binding sites (Biochemistry), Phosphoinositides
Journal or Publication Title: Science Advances
Publisher: American Association for the Advancement of Science
ISSN: 2375-2548
Official Date: 19 February 2020
Dates:
DateEvent
19 February 2020Published
12 November 2019Accepted
Date of first compliant deposit: 12 November 2019
Volume: 6
Number: 8
Article Number: eaay5736
DOI: 10.1126/sciadv.aay5736
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/ZMedical Research Councilhttp://dx.doi.org/10.13039/501100000265
208361/Z/17/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
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
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