OSBP-Related Proteins: Liganding by Glycerophospholipids Opens New Insight into Their Function

Vesa Olkkonen

doi:10.3390/molecules181113666

Abstract

Oxysterol-binding protein (OSBP) and its homologs designated OSBP-related (ORP) or OSBP-like (OSBPL) proteins constitute a conserved family of lipid binding/transfer proteins (LTP) in eukaryotes. The mechanisms of ORP function have remained incompletely understood, but they have been implicated as intracellular sterol sensors or transporters. A number of studies have provided evidence for the roles of ORPs at membrane contact sites (MCS), where endoplasmic reticulum is closely apposed with other organelle limiting membranes. ORPs are postulated to either transport sterols over MCSs or control the activity of enzymatic effectors or assembly of protein complexes with functions in signaling and lipid metabolism. Studies of yeast Saccharomyces cerevisiae ORPs Osh4p, Osh3p, Osh6p and Osh7p have revealed that ORPs do not exclusively bind sterols within their OSBP-related ligand-binding domain (ORD): The Osh4p ORD accommodates either sterols or phosphatidylinositol-4-phosphate (PI4P), and the Osh3p ORD was shown to specifically bind PI4P, the binding cavity being too narrow for a sterol to fit in. Most recently, Osh6p and Osh7p were demonstrated to show specific affinity for phosphatidylserine (PS), and to play a role in the intracellular transport of this glycerophospholipid; Additionally, two mammalian ORPs were shown to bind PS. Thus, the term frequently used for ORPs/OSBPLs, oxysterol-binding proteins, is a misnomer. While a number of ORPs bind oxysterols or cholesterol, other family members appear to interact with phospholipid ligands to regulate lipid fluxes, organelle lipid compositions and cell signaling. As a conclusion, ORPs are LTPs with a wide ligand spectrum and marked functional heterogeneity.

Highlights

The compartmentalization of lipid synthetic processes and the inter-organelle distributions of lipids in eukaryotic cells necessitate well controlled lipid fluxes [1]
The intracellular transport of lipids is mediated by four major mechanisms: (i) Flip-flop from one leaflet of a bilayer to the other [2,3]; (ii) movement as components of transport vesicles/tubular carriers [4,5]; (iii) diffusion along membrane bilayers and between closely apposed membrane leaflets [1], (iv) transfer by lipid binding/transfer proteins (LTPs) [6,7]
Cholesterol is markedly hydrophobic, and even though part of it is transported within cells along with vesicular/tubular carriers of the vesicle transport pathways, its efficient inter-organelle transport needs to be mediated to a large extent by non-vesicular processes facilitated e.g., by LTPs and/or closely apposed membrane domains, similar to the transport of glycero- and sphingolipids with physiologic, long-chain fatty acyl chains [7,15,16]

Summary

Introduction

The compartmentalization of lipid synthetic processes and the inter-organelle distributions of lipids in eukaryotic cells necessitate well controlled lipid fluxes [1]. (ii) movement as components of transport vesicles/tubular carriers [4,5]; (iii) diffusion along membrane bilayers and between closely apposed membrane leaflets [1], (iv) transfer by lipid binding/transfer proteins (LTPs) [6,7] The latter two mechanisms represent non-vesicular inter-bilayer lipid transport and play important roles in lipid fluxes between organelles not connected via the established pathways of membrane trafficking. Cholesterol is markedly hydrophobic, and even though part of it is transported within cells along with vesicular/tubular carriers of the vesicle transport pathways, its efficient inter-organelle transport needs to be mediated to a large extent by non-vesicular processes facilitated e.g., by LTPs and/or closely apposed membrane domains, similar to the transport of glycero- and sphingolipids with physiologic, long-chain fatty acyl chains [7,15,16]. Oxysterols, especially those modified by hydroxylation of the sterol side chain, have crucial signaling functions via liganding of transcription factors and protein regulators of metabolism [20,30]

OSBP-Related Proteins and Their Liganding by Sterols

ORPs Can Bind Glycerophospholipids

Function of ORPs at Membrane Contact Sites

Conclusions