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


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)P2], 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)P2 synthesis that ultimately controls global PM organization and dynamics.

SUBMITTER: Nishimura T 

PROVIDER: S-EPMC6739424 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P<sub>2</sub> Synthesis.

Nishimura Taki T   Gecht Michael M   Covino Roberto R   Hummer Gerhard G   Surma Michal A MA   Klose Christian C   Arai Hiroyuki H   Kono Nozomu N   Stefan Christopher J CJ  

Molecular cell 20190808 5


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<sub>2</sub>], a key regulator of dynamic events at the PM. In real-time assays, we find that unsaturated phosphatidylserine (PS) and sterols  ...[more]

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