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.

Development of Chemical Probes for Functional Analysis of Anticancer Saponin OSW‐1

“…In 2010, Shair et al reported that OSBP and ORP4 L, two members of the oxysterol binding protein (ORP) superfamily implicated in lipid/sterol transport and sensing are the major protein targets of OSW-1. [4,5] Using competitive binding assays based on recombinant OSBP and ORP4 L and [ 3 H]-25-HC, their endogenous ligand, OSW-1 exhibits high affinity toward these proteins (K i = 26 nM for OSBP and 54 nM for ORP4 L). However, the link between the inhibition of OSBP and ORP4 L and apoptotic induction has remained unclear.…”

Transient Compound Treatment Induces a Multigenerational Reduction of Oxysterol-Binding Protein (OSBP) Levels and Prophylactic Antiviral Activity

“…Therefore, the long-term, compound-induced reduction of OSBP in cells presents a new route to broad spectrum anti-Enterovirus activity, including as a novel route to antiviral prophylactic treatment through small molecule targeting a human host protein.O xysterol-binding protein (OSBP) and the OSBP-related proteins (ORPs) are a family of lipid and sterol binding proteins conserved in all eukaryotes. 1,2 The 12 OSBP/ORP human proteins share a conserved ∼50 kDa, C-terminal ligand binding domain. 1,2 OSBP and ORP4, the member most closely related to OSBP, share substantial sequence similarity, and both contain N-terminal pleckstrin homology (PH) and FFAT domains.…”

“…3−5 The PH and FFAT domains alter OSBP cellular localization upon binding of ligands in the C-terminal ligand binding domain. 1,2 OSBP binding partners, including several regulatory proteins, have been reported. 1,2 OSBP gene expression and protein regulation are not well-defined.…”

“…2,10 OSBP is expressed in all tissues, but ORP4 is expressed in only a few select human tissues. 1,2 ORP4 is highly expressed in some cancer cells and shown to be required for cancer cell line proliferation. 2,10 ORP4 is selectively overex- Figure 1.…”

“…1,2 ORP4 is highly expressed in some cancer cells and shown to be required for cancer cell line proliferation. 2,10 ORP4 is selectively overex- Figure 1. Brief exposure to nontoxic, low-nanomolar OSW-1 compound concentrations causes long-term OSBP reduction in multiple cell lines.…”