1. Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P2 Synthesis.
- Author
-
Nishimura, Taki, Gecht, Michael, Covino, Roberto, Hummer, Gerhard, Surma, Michal A., Klose, Christian, Arai, Hiroyuki, Kono, Nozomu, and Stefan, Christopher J.
- Subjects
- *
MOLECULAR dynamics , *MEMBRANE lipids , *BILAYER lipid membranes , *LIPIDS , *PROTEINS , *CELL membranes , *PHOSPHOINOSITIDES - 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. • The Osh lipid exchange proteins are required to maintain PI(4,5)P 2 levels in the PM • Unsaturated PS and sterols synergistically stimulate PIP5K activity • The specificity loop conserved in PIP5Ks serves as a lipid sensor • A simulation model of the PIP5K specificity loop embedded in a lipid bilayer Nishimura et al. show that the Osh lipid exchange proteins are required for PI(4,5)P 2 synthesis, a key regulator of global plasma membrane organization and function. The Osh proteins form a unique membrane lipid environment with unsaturated phosphatidylserine and sterols that specifies PIP 5-kinase activity at the plasma membrane. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF