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Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P 2 Synthesis

61 Pages Posted: 16 Jan 2019 Sneak Peek Status: Published

See all articles by Taki Nishimura

Taki Nishimura

University College London - MRC LMCB - Laboratory for Molecular Cell Biology

Roberto Covino

Max Planck Institute of Biophysics - Department of Theoretical Biophysics

Michael Gecht

Max Planck Institute of Biophysics - Department of Theoretical Biophysics

Gerhard Hummer

Max Planck Institute of Biophysics - Department of Theoretical Biophysics; Goethe University Frankfurt - Institute for Biophysics

Hiroyuki Arai

University of Tokyo - Department of Health Chemistry; Japan Agency for Medical Research and Development - AMED-CREST

Nozomu Kono

University of Tokyo - Department of Health Chemistry; Japan Agency for Medical Research and Development - PRIME

Christopher Stefan

University College London - MRC LMCB - Laboratory for Molecular Cell Biology

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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/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 ORP/Osh protein ligands, synergistically stimulate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity. Our biophysical and simulation analyses further reveal an unconventional co-segregation of unsaturated PS and phosphatidylinositol 4-phosphate (PI4P) species in sterol-containing membrane bilayers. Moreover, we show that Osh protein-mediated unsaturated PI4P/PS membrane lipid organization is sensed by the PIP5K specificity loop. Thus, ORP/Osh family members create an unsaturated phospholipid nanoscale environment that drives PIP5K activity and PI(4,5)P2 synthesis that ultimately controls global PM organization and dynamics.

Keywords: endoplasmic reticulum/ oxysterol-binding protein homology protein/ phosphatidylserine/ PIP5K, phosphatidylinositol 4-phosphate 5-kinase/ plasma membrane/ sterol/ unsaturated phospholipid

Suggested Citation

Nishimura, Taki and Covino, Roberto and Gecht, Michael and Hummer, Gerhard and Arai, Hiroyuki and Kono, Nozomu and Stefan, Christopher, Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P 2 Synthesis (January 16, 2019). Available at SSRN: https://ssrn.com/abstract=3316809 or http://dx.doi.org/10.2139/ssrn.3316809
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Taki Nishimura

University College London - MRC LMCB - Laboratory for Molecular Cell Biology ( email )

Gower St
Kings Cross
London, WC1E 6BT
United Kingdom

Roberto Covino

Max Planck Institute of Biophysics - Department of Theoretical Biophysics

Frankfurt am Main
Germany

Michael Gecht

Max Planck Institute of Biophysics - Department of Theoretical Biophysics

Frankfurt am Main
Germany

Gerhard Hummer

Max Planck Institute of Biophysics - Department of Theoretical Biophysics

Frankfurt am Main
Germany

Goethe University Frankfurt - Institute for Biophysics

Frankfurt am Main
Germany

Hiroyuki Arai

University of Tokyo - Department of Health Chemistry

Tokyo, 113-0033
Japan

Japan Agency for Medical Research and Development - AMED-CREST

1-7-1 Otemachi
Tokyo, 100-0004
Japan

Nozomu Kono

University of Tokyo - Department of Health Chemistry

Tokyo, 113-0033
Japan

Japan Agency for Medical Research and Development - PRIME

1-7-1 Otemachi
Tokyo, 100-0004
Japan

Christopher Stefan (Contact Author)

University College London - MRC LMCB - Laboratory for Molecular Cell Biology ( email )

Gower St
Kings Cross
London, WC1E 6BT
United Kingdom

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