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

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.

SUBMITTER: Yamamoto E

PROVIDER: S-EPMC7030919 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Yamamoto Eiji E Domański Jan J Naughton Fiona B FB Best Robert B RB Kalli Antreas C AC Stansfeld Phillip J PJ Sansom Mark S P MSP

Science advances 20200219 8

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 PIP<sub>3</sub>-containing membranes. The free energy of interaction of the PH domain with more than two PIP<sub> ...[more]

PMID: 32128410

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Project description:Highlights • Metal induced changes of membrane fluidity in phosphoinositide dependent manner.• Metals induced phase separation and cluster formation in PI containing membranes.• Metal induced liposome aggregation in phosphoinositide dependent manner. This work assessed effects of metal binding on membrane fluidity, liposome size, and lateral organization in biomimetic membranes composed of 1 mol% of selected phosphorylated phosphoinositides in each system. Representative examples of phosphoinositide phosphate, bisphosphate and triphosphate were investigated. These include phosphatidylinositol-(4,5)-bisphosphate, an important signaling lipid constituting a minor component in plasma membranes whereas phosphatidylinositol-(4,5)-bisphosphate clusters support the propagation of secondary messengers in numerous signaling pathways. The high negative charge of phosphoinositides facilitates electrostatic interactions with metals. Lipids are increasingly identified as toxicological targets for divalent metals, which potentially alter lipid packing and domain formation. Exposure to heavy metals, such as lead and cadmium or elevated levels of essential metals, like cobalt, nickel, and manganese, implicated with various toxic effects were investigated. Phosphatidylinositol-(4)-phosphate and phosphatidylinositol-(3,4,5)-triphosphate containing membranes are rigidified by lead, cobalt, and manganese whilst cadmium and nickel enhanced fluidity of membranes containing phosphatidylinositol-(4,5)-bisphosphate. Only cobalt induced liposome aggregation. All metals enhanced lipid clustering in phosphatidylinositol-(3,4,5)-triphosphate systems, cobalt in phosphatidylinositol-(4,5)-bisphosphate systems, while all metals showed limited changes in lateral film organization in phosphatidylinositol-(4)-phosphate matrices. These observed changes are relevant from the biophysical perspective as interference with the spatiotemporal formation of intricate domains composed of important signaling lipids may contribute to metal toxicity. Graphical abstracts Image, graphical abstract

Dataset Information

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

Publications

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

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