Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins

• Published in: Nature (London) Vol. 501; no. 7466; pp. 257 - 261
• Main Authors: Maeda, Kenji, Anand, Kanchan, Chiapparino, Antonella, Kumar, Arun, Poletto, Mattia, Kaksonen, Marko, Gavin, Anne-Claude
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.09.2013; Nature Publishing Group
• Subjects: 631/45/287/1192; 631/45/535/1266; 631/45/608; 631/553/2710; Binding proteins; Biological membranes; Biological Transport; Biosynthesis; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Cell Membrane - metabolism; Dyslipidemias - metabolism; Endoplasmic Reticulum - metabolism; Eukaryotes; Fractionation; Homeostasis; Humanities and Social Sciences; Humans; Interactomes; letter; Ligands; Lipid metabolism; Lipids; Membranes; Metabolic disorders; Metabolic Syndrome - metabolism; multidisciplinary; Neoplasms - metabolism; Phosphatidylserines; Phosphatidylserines - metabolism; Phylogeny; Physiological aspects; Properties; Protein Interaction Maps; Proteins; Receptors, Steroid - chemistry; Receptors, Steroid - metabolism; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - metabolism; Science; Sterols; Substrate Specificity; Yeast; Yeasts; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature12430

The lipid-binding profiles of all lipid-transfer proteins in Saccharomyces cerevisiae are determined and a new subfamily of oxysterol-binding proteins that function in phosphatidylserine homeostasis and transport is identified. A novel family of phosphatidylserine transport proteins Eukaryotic cells are compartmentalized internally by a series of functionally specialized membrane-bound organelles with unique lipid composition. In this study, Anne-Claude Gavin and colleagues determine the lipid-binding profiles of all lipid-transfer proteins in the budding yeast Saccharomyces cerevisiae , and identify a previously unrecognized subfamily of oxysterol-binding proteins (OSBPs) that function in phosphatidylserine homeostasis and transport rather than in the transfer of sterols. Phylogenetic analysis shows that similar OSPBs are broadly conserved — including in humans where they are associated with pathologies including cancer and metabolic syndrome. The internal organization of eukaryotic cells into functionally specialized, membrane-delimited organelles of unique composition implies a need for active, regulated lipid transport. Phosphatidylserine (PS), for example, is synthesized in the endoplasmic reticulum and then preferentially associates—through mechanisms not fully elucidated—with the inner leaflet of the plasma membrane 1 , 2 , 3 . Lipids can travel via transport vesicles. Alternatively, several protein families known as lipid-transfer proteins (LTPs) can extract a variety of specific lipids from biological membranes and transport them, within a hydrophobic pocket, through aqueous phases 4 , 5 , 6 , 7 . Here we report the development of an integrated approach that combines protein fractionation and lipidomics to characterize the LTP–lipid complexes formed in vivo . We applied the procedure to 13 LTPs in the yeast Saccharomyces cerevisiae : the six Sec14 homology (Sfh) proteins and the seven oxysterol-binding homology (Osh) proteins. We found that Osh6 and Osh7 have an unexpected specificity for PS. In vivo , they participate in PS homeostasis and the transport of this lipid to the plasma membrane. The structure of Osh6 bound to PS reveals unique features that are conserved among other metazoan oxysterol-binding proteins (OSBPs) and are required for PS recognition. Our findings represent the first direct evidence, to our knowledge, for the non-vesicular transfer of PS from its site of biosynthesis (the endoplasmic reticulum) to its site of biological activity (the plasma membrane). We describe a new subfamily of OSBPs, including human ORP5 and ORP10, that transfer PS and propose new mechanisms of action for a protein family that is involved in several human pathologies such as cancer, dyslipidaemia and metabolic syndrome.