title: A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP.
abstract: Several proteins at endoplasmic reticulum (ER)-Golgi membrane contact sites contain a PH domain that interacts with the Golgi phosphoinositide PI(4)P, a FFAT motif that interacts with the ER protein VAP-A, and a lipid transfer domain. This architecture suggests the ability to both tether organelles and transport lipids between them. We show that in oxysterol binding protein (OSBP) these two activities are coupled by a four-step cycle. Membrane tethering by the PH domain and the FFAT motif enables sterol transfer by the lipid transfer domain (ORD), followed by back transfer of PI(4)P by the ORD. Finally, PI(4)P is hydrolyzed in cis by the ER protein Sac1. The energy provided by PI(4)P hydrolysis drives sterol transfer and allows negative feedback when PI(4)P becomes limiting. Other lipid transfer proteins are tethered by the same mechanism. Thus, OSBP-mediated back transfer of PI(4)P might coordinate the transfer of other lipid species at the ER-Golgi interface.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, 06560 Valbonne, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Mesmin
authors.forename: Joëlle
authors.initials: J
authors.lastname: Bigay
authors.forename: Joachim
authors.initials: J
authors.lastname: Moser von Filseck
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.forename: Guillaume
authors.initials: G
authors.lastname: Drin
authors.forename: Bruno
authors.initials: B
authors.lastname: Antonny
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D008969:Molecular Sequence Data; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013261:Sterols / Q000378:metabolism; D000098825:Oxysterol Binding Proteins
chemical_list: D018129:Phosphatidylinositol Phosphates; D011987:Receptors, Steroid; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; D000098825:Oxysterol Binding Proteins; C037178:phosphatidylinositol 4-phosphate; D006160:Guanosine Triphosphate; C081864:SAC1 protein, S cerevisiae; D010744:Phosphoric Monoester Hydrolases; D020823:ADP-Ribosylation Factor 1