Bridging the molecular and biological functions of the oxysterol-binding protein family

Abstract

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a large eukaryotic gene family that transports and regulates the metabolism of sterols and phospholipids. The original classification of the family based on oxysterol-binding activity belies the complex dual lipid-binding specificity of the conserved OSBP homology domain (OHD). Additional protein- and membrane-interacting modules mediate the targeting of select OSBP/ORPs to membrane contact sites between organelles, thus positioning the OHD between opposing membranes for lipid transfer and metabolic regulation. This unique subcellular location, coupled with diverse ligand preferences and tissue distribution, has identified OSBP/ORPs as key arbiters of membrane composition and function. Here, we will review how molecular models of OSBP/ORP-mediated intracellular lipid transport and regulation at membrane contact sites relate to their emerging roles in cellular and organismal functions.

Keywords: Cancer; Dyslipidemia; Intracellular lipid transport; Membrane contact sites; Metabolism; Oxysterol-binding proteins; Viral replication.

Fig. 1

Structural organization of the OSBP/ORP family. a Domain structure of the OSBP/ORP family. OHD OSBP homology domsin, PH pleckstrin homology, FFAT two phenylalanines in an acidic tract, Ank ankyrin, TM transmembrane. b Shown is the structure of the S. cerevisiae Osh4p OHD composed of an incomplete β-barrel (green) flanked by two central helices (yellow), N-terminal region (blue) and α-helical lid (red). The OHD binds sterols and phospholipids competitively and in opposite orientations; the acyl chains of phospholipids are buried in the pocket, while the iso-octyl side chain of sterols interacts with the lid

Fig. 2

Subcellular localization of the OSBP/ORP family. Aside from ORP5 and ORP8, all ORPs display partial cytosolic localization, but most also have discrete localization patterns, including membrane contact sites between organelles, on cytoskeletal elements and in the nucleus (see figure for details). For simplicity, only well-characterized localization patterns relevant to known or predicted protein functions have been included. ORP3 and ORP7 do not have well-defined localization patterns and have been omitted

Fig. 3

Models of ORP function at membrane contact sites. OSBP localizes to closely apposed ER/Golgi membranes, where it exchanges PI(4)P and cholesterol. The resulting cholesterol enrichment on the Golgi activates PI4KIIα, which phosphorylates PI delivered by Nir2, into a PI(4)P pool that recruits the ceramide transfer protein CERT, resulting in ceramide delivery to sphingomyelin (SM) synthase and consequent SM synthesis. Consumption of PI(4)P in the endoplasmic reticulum (ER) by the Sac1 phosphatase maintains a concentration gradient that drives the PI(4)P/cholesterol counter-current transport. Yeast Osh4p functions similarly to OSBP but without tethering to the ER or Golgi apparatus. ORP5 and ORP8 are ER-tethered proteins that extend to the plasma membrane via PH domain interaction with PIPs, using the transport of PI(4)P to the ER to drive phosphatidylserine transport to the PM. ORP1L is localized to the late endosomes/lysosomes (LEL) via interaction between N-terminal ankyrin repeats and Rab7. When cholesterol is low in the limiting membrane of LEL, ORP1L promotes the assembly of a microtubule-tethering complex (Rab7/RILP/p150^glued) that facilitates minus-end movement of the LEL. When cholesterol on the LEL limiting membrane is elevated, the complex dissembles and ORP1L tethers the LEL to the ER via VAP and facilitates cholesterol efflux to the ER