Oxysterol-binding protein 1 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''OSBP''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Function

Oxysterol-binding protein (OSBP) is an intracellular protein that was identified as a cytosolic 25-hydroxycholesterol-binding protein. OSBP is a lipid transfer protein that controls cholesterol/PI4P exchange at ER-Golgi

membrane contact site Membrane contact sites (MCS) are close appositions between two organelles. Ultrastructural studies typically reveal an intermembrane distance in the order of the size of a single protein, as small as 10 nm or wider, with no clear upper limit. ...

s. 25-hydroxycholesterol acts as a natural inhibitor of this exchange. OSBP regulates ER-Golgi membrane contact sites formation by bridging ER and Golgi membranes together. OSBP plays also a role as a sterol-regulated scaffolding protein for several cytosolic reactions including the phosphorylation of ERK 1/2. It has been shown that expression and maturation of SREBP-1c is controlled by OSBP. SREBP-1c is a major transcription factor for hepatic

lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride syn ...

(fatty acids and triglycerides biosynthesis). OSBP expression levels in transgenic mice affect liver and serum TG levels. OSBP is thought to be an essential scaffolding compound of the protein complex that regulates the activation state of the ERK protein. OSBP also acts as a sterol-dependant scaffold for the

JAK2 Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF rec ...

and

STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...

proteins.

Mechanism of action

OSBP is a multi-domain protein consisting of an N-terminal

pleckstrin homology Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phospha ...

(PH) domain, a central

FFAT motif A FFAT motif (FFAT being an acronym for two phenylalanines (FF) in an acidic tract) is a protein sequence motif of six defined amino acids plus neighbouring residues that binds to proteins in the VAP protein family. Initial definition The class ...

(two phenylalanines in an acidic track), and a C-terminal lipid transport domain (ORD). The PH domain binds the trans- Golgi membrane by contacting the lipid PI4P and the activated small G protein

Arf1 ADP-ribosylation factor 1 is a protein that in humans is encoded by the ''ARF1'' gene. Function ADP-ribosylation factor 1 (ARF1) is a member of the human ARF gene family. The family members encode small guanine nucleotide-binding proteins that ...

(-GTP), whereas the

binds the type II ER membrane protein VAP-A. OSBP bridges the Golgi and the ER by establishing contacts with all of these determinants simultaneously. OSBP is thought to transport cholesterol from the ER to the Golgi, and to transport the phosphoinositide PI4P backward (from the Golgi to the ER). Then, PI4P can be hydrolyzed by the phosphatidylinositide phosphatase SAC1, which is an ER-resident protein. Therefore, OSBP acts as a negative regulator of its own attachment to the trans-Golgi (which requires the binding of its PH domain to PI4P). This negative feedback system might coordinate cholesterol transport out of the ER to PI4P level in the Golgi.

Regulation

OSBP is regulated by PKD mediated phosphorylation, and by the oxysterol 25-hydroxycholesterol (25-OH), a high-affinity ligand for OSBP (~30 nM). Several proteins involved in cholesterol homeostasis, such as

INSIG-1 Insulin induced gene 1, also known as INSIG1, is a protein which in humans is encoded by the ''INSIG1'' gene. INSIG1 is short for insulin-induced gene 1; it is located on chromosome 7 (7q36). This human gene encodes for a transmembrane protein of ...

or ACAT, also bind 25-OH. In fact 25-OH is a potent suppressor of sterol synthesis in cultured cells and accelerates cholesterol esterification. In cellular studies it has been shown that OSBP, initially cytosolic, relocates to ER-Golgi membrane contact sites in the presence of 25-OH. 25-OH acts as an inhibitor of sterol transport mediated by OSBP in vitro.

Isoforms

OSBP is the founding member of the ORP (OSBP-related proteins) family of lipid transfer proteins. Mammals have 16 different ORPs, whereas the yeast S. cerevisiae genome encodes seven ORP homologues (Osh). ORP and Osh proteins contain a lipid transport domain called ORD (OSBP-related domain) encompassing the EQVSHHPP signature sequence. The ORD structure consists in a hydrophobic pocket. Because the EQVSHHPP sequence is crucial for PI4P binding to the ORD, but not for sterol binding, it has been proposed that PI4P transport is a common function of Osh/ORP proteins.

Function

Mechanism of action

Regulation

Isoforms

References

Further reading