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Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P₂ Synthesis

Nishimura, T; Gecht, M; Covino, R; Hummer, G; Surma, MA; Klose, C; Arai, H; ... Stefan, CJ; + view all (2019) Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P₂ Synthesis. Molecular Cell 10.1016/j.molcel.2019.06.037. (In press). Green open access

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Abstract

The plasma membrane (PM) is composed of a complex lipid mixture that forms heterogeneous membrane environments. Yet, how small-scale lipid organization controls physiological events at the PM remains largely unknown. Here, we show that ORP-related Osh lipid exchange proteins are critical for the synthesis of phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P_{2}], a key regulator of dynamic events at the PM. In real-time assays, we find that unsaturated phosphatidylserine (PS) and sterols, both Osh protein ligands, synergistically stimulate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity. Biophysical FRET analyses suggest an unconventional co-distribution of unsaturated PS and phosphatidylinositol 4-phosphate (PI4P) species in sterol-containing membrane bilayers. Moreover, using in vivo imaging approaches and molecular dynamics simulations, we show that Osh protein-mediated unsaturated PI4P and PS membrane lipid organization is sensed by the PIP5K specificity loop. Thus, ORP family members create a nanoscale membrane lipid environment that drives PIP5K activity and PI(4,5)P_{2} synthesis that ultimately controls global PM organization and dynamics.

Type: Article
Title: Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P₂ Synthesis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.molcel.2019.06.037
Publisher version: https://doi.org/10.1016/j.molcel.2019.06.037
Language: English
Additional information: © 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: endoplasmic reticulum, oxysterol-binding protein homology protein, phosphatidylserine, phosphatidylinositol 4-phosphate 5-kinase, plasma membrane, sterol, unsaturated phospholipid
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10079969
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