Lipid-regulated sterol transfer between closely apposed membranes by oxysterol-binding protein homologues.
Sterols are transferred between cellular membranes by vesicular and poorly understood nonvesicular pathways. Oxysterol-binding protein-related proteins (ORPs) have been implicated in sterol sensing and nonvesicular transport. In this study, we show that yeast ORPs use a novel mechanism that allows regulated sterol transfer between closely apposed membranes, such as organelle contact sites. We find that the core lipid-binding domain found in all ORPs can simultaneously bind two membranes. Using Osh4p/Kes1p as a representative ORP, we show that ORPs have at least two membrane-binding surfaces; one near the mouth of the sterol-binding pocket and a distal site that can bind a second membrane. The distal site is required for the protein to function in cells and, remarkably, regulates the rate at which Osh4p extracts and delivers sterols in a phosphoinositide-dependent manner. Together, these findings suggest a new model of how ORPs could sense and regulate the lipid composition of adjacent membranes.
Schulz
Timothy A
TA
Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Choi
Mal-Gi
MG
Raychaudhuri
Sumana
S
Mears
Jason A
JA
Ghirlando
Rodolfo
R
Hinshaw
Jenny E
JE
Prinz
William A
WA
D001665:Binding Sites; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007700:Kinetics; D008081:Liposomes / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D010716:Phosphatidylinositols / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011987:Receptors, Steroid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*; D000098825:Oxysterol Binding Proteins
D002352:Carrier Proteins; D008081:Liposomes; D008563:Membrane Lipids; D008565:Membrane Proteins; D010716:Phosphatidylinositols; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; C087901:KES1 protein, S cerevisiae; D000098825:Oxysterol Binding Proteins