Cytoplasmic oxysterol-binding proteins: sterol sensors or transporters?

► Most ORPs are able to bind oxysterols, cholesterol, or both in a conserved ligand binding domain. ► ORPs have functions in cellular lipid metabolism, vesicle transport, and cell signaling. ► ORPs are suggested to localize and function at contact sites that the ER forms with other organelles. ► ORPs interact with PIPs and increasing evidence suggests their involvement in metabolism of PIPs. ► ORPs are suggested to act as intracellular sterol transporters and/or mediators of sterol signals. Families of oxysterol-binding protein (ORP) homologues are present in eukaryotes from yeast to man. Their hallmark feature is a characteristic ligand binding domain that, for several family members, has been shown to accommodate different oxysterols and/or cholesterol. ORPs of the “long” subtype contain targeting determinants for the endoplasmic reticulum and to other organelle membranes, the most prominent of which are phosphoinositide-binding pleckstrin homology domains, while “short” ORPs comprise a ligand binding domain with little additional sequences. There is increasing evidence that both long and short ORPs can be enriched at membrane contact sites, junctions of the endoplasmic reticulum with other organelles, where they are suggested to execute regulatory or sterol transfer functions. In this review we discuss the current evidence for putative roles of ORPs as sterol sensors or transporters.