OSBP-Related Protein Family in Lipid Transport Over Membrane Contact Sites

Abstract

Increasing evidence suggests that oxysterol-binding protein-related proteins (ORPs) localize at membrane contact sites, which are high-capacity platforms for inter-organelle exchange of small molecules and information. ORPs can simultaneously associate with the two apposed membranes and transfer lipids across the interbilayer gap. Oxysterol-binding protein moves cholesterol from the endoplasmic reticulum to trans-Golgi, driven by the retrograde transport of phosphatidylinositol-4-phosphate (PI4P). Analogously, yeast Osh6p mediates the transport of phosphatidylserine from the endoplasmic reticulum to the plasma membrane in exchange for PI4P, and ORP5 and -8 are suggested to execute similar functions in mammalian cells. ORPs may share the capacity to bind PI4P within their ligand-binding domain, prompting the hypothesis that bidirectional transport of a phosphoinositide and another lipid may be a common theme among the protein family. This model, however, needs more experimental support and does not exclude a function of ORPs in lipid signaling.

Keywords: OSBP-related protein; OSBPL gene; lipid signaling; lipid transport; membrane contact site; oxysterol-binding protein (OSBP).

Figure 1

Structural organization of the ORPs. (A) Schematic diagram of the structure of mammalian and yeast ORPs. In the nomenclature of the proteins, L indicates “long” isoforms that contain a PH domain and S indicates “short” isoforms lacking this domain. Mammalian proteins are indicated with black, and yeast ones with blue print on the right. PH, pleckstrin homology domain; D, dimerization; L, leucine repeat domains delineated in OSBP and ORP4L; FFAT, “two phenylalanines in an acidic tract”; ORD, OSBP-related ligand-binding domain; ANK, ankyrin repeats; TM, trans-membrane segment. (B) A model of how OSBP is thought to bridge between ER and trans-Golgi membranes at a contact site (based on Ref. 32). Both OSBP and VAPs anchoring it to ER membranes are suggested to operate as dimers. PI4P, phosphatidylinositol 4-phosphate; Arf, the small GTPase ADP-ribosylation factor; MSP, major sperm protein domain; VAP, VAMP-associated protein.

Figure 2

Models for the function of ORPs at membrane contact sites (MSCs). (A) OSBP transfers cholesterol (C) within its ligand-binding domain (ORD) over MCSs from the ER to trans-Golgi and PI4P in the opposite direction (based on Ref. 32). The phosphatidylinositol 4-phosphate (PI4P) retrogradely transported to the ER is hydrolyzed by the phosphatase Sac1 to phoshatidylinositol (PI) and inorganic phosphate. The PI4P gradient between Golgi and ER thus drives the forward transport of cholesterol against its concentration gradient. The fact that OSBP is targeted to the Golgi through binding of its pleckstrin homology (PH) domain to PI4P provides a mechanism of autoregulation of the process. FFAT, “two phenylalanines in an acidic tract,” motif mediating the interaction of OSBP with the VAMP-associated proteins (VAP) in the ER. (B) Models for ORP function as regulators of enzymatic or signaling processes at MCSs. An ORP binds a lipidous ligand (L), which regulates the conformation of the protein, allowing it to stimulate at an ER–plasma membrane contact (a) the activity of an enzyme (E) that is anchored in ER membranes and modifies in trans the structure of lipid substrates in the plasma membrane (based on Refs. , on yeast Osh3p), or (b) the activation of a signaling component, eg, a small GTPase (G; based on Ref. on ORP3). X, an activator of the GTPase. The inactive enzyme and GTPase are depicted in green and the active ones in orange. Regulation of the processes by the ligand (L) is in the cases of Osh3p and ORP3 hypothetical, and whether L is transported over the contact site is unknown.