TY  - JOUR
A1  - Nishimura, Taki
A1  - Gecht, Michael
A1  - Covino, Roberto
A1  - Hummer, Gerhard
A1  - Surma, Michał
A1  - Klose, Christian
A1  - Arai, Hiroyuki
A1  - Kono, Nozomu
A1  - Stefan, Christopher J.
T1  - Osh proteins control nanoscale lipid organization necessary for PI(4,5)P2 synthesis
T2  - Molecular cell
N2  - 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.
KW  - endoplasmic reticulum
KW  - oxysterol-binding protein homology protein
KW  - phosphatidylinositol 4-phosphate 5-kinase
KW  - phosphatidylserine
KW  - plasma membrane
KW  - sterol
KW  - unsaturated phospholipid
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50854
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-508542
SN  - 1097-4164
SN  - 1097-2765
N1  - This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
VL  - 75
IS  - 5
SP  - 1043
EP  - 1057.e8
PB  - Cell Press ; Elsevier
CY  - [Cambridge, Mass.] ; New York, NY
ER  -