Nishimura, T; Gecht, M; Covino, R; Hummer, G; Surma, MA; Klose, C; Arai, H; ... Stefan, CJ; + view all Nishimura, T; Gecht, M; Covino, R; Hummer, G; Surma, MA; Klose, C; Arai, H; Kono, N; Stefan, CJ; - view fewer (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).

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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.

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