# OSBP

## Overview
OSBP, or Oxysterol Binding Protein, is a gene that encodes a multifunctional cytosolic protein involved in the regulation of lipid and cholesterol metabolism. The protein, also named OSBP, is characterized by its ability to bind oxysterols, which are oxygenated derivatives of cholesterol, and plays a critical role in the transport and regulation of sterols between cellular organelles such as the endoplasmic reticulum and Golgi apparatus. Structurally, OSBP features a conserved OSBP homology domain (OHD) for sterol binding, a pleckstrin homology (PH) domain for membrane targeting, and a FFAT motif for interaction with vesicle-associated membrane proteins. These domains facilitate OSBP's role in lipid signaling and cellular homeostasis, making it a key player in both physiological and pathological processes (Ridgway2010Oxysterol-Binding; Pietrangelo2018Bridging).

## Structure
The OSBP protein is characterized by a conserved C-terminal OSBP homology domain (OHD), which is crucial for binding cholesterol and oxysterols. This domain, based on the structure of the yeast homologue Osh4p, includes a 270 amino acid, 19-strand β-barrel topped by a flexible α-helical lid. The interior of the β-barrel is hydrophobic and accommodates up to 15 water molecules, facilitating interactions between the sterol's 3-hydroxyl group and the amino acids lining the binding site. The α-helical lid can close over the binding site, interacting with the sterol ligand through van der Waals forces (Ridgway2010Oxysterol-Binding).

Additionally, OSBP contains a pleckstrin homology (PH) domain that specifically recognizes phosphatidylinositol phosphates (PIPs) with varying specificity and affinity. This domain is involved in membrane targeting (Pietrangelo2018Bridging). The protein also features a FFAT motif that interacts with the ER protein vesicle-associated membrane protein-associated protein (VAP), facilitating the peripheral anchoring of these proteins at the ER (Pietrangelo2018Bridging).

OSBP undergoes post-translational modifications such as phosphorylation, which may regulate its interaction with other proteins and lipids (Antonny2018The). The protein is encoded by multiple splice variants, leading to different isoforms that may affect its structure and function (Ngo2010Functional).

## Function
OSBP (Oxysterol Binding Protein) is a cytosolic protein that plays a pivotal role in the regulation of lipid and cholesterol metabolism within cells. It functions as a high-affinity receptor for oxysterols, such as 25-hydroxycholesterol, and upon binding these ligands, OSBP translocates from the cytosol to the Golgi apparatus. This translocation is crucial for its role in modulating lipid composition and facilitating sterol transport between the endoplasmic reticulum (ER) and the Golgi apparatus (WANG2002Oxysterol-binding-protein; Laitinen1999Family).

At the Golgi, OSBP is involved in the regulation of cholesterol homeostasis by influencing the activity of enzymes and receptors involved in cholesterol biosynthesis and uptake, such as LDL receptor and HMG-CoA reductase (Lehto2003The). Additionally, OSBP participates in the architecture of ER-Golgi contact sites, which are critical for inter-organellar communication and lipid transfer (Delfosse2020Structural).

OSBP also impacts cellular signaling pathways. It acts as a sterol sensor and regulates the activity of extracellular signal-regulated kinases (ERKs) through its interactions with cholesterol, which modulates cell proliferation and survival (Kentala2016OSBP-Related). Furthermore, OSBP's interaction with phosphatidylinositol 4-phosphate (PI(4)P) at the Golgi and its exchange with the ER is essential for maintaining the lipid composition of the Golgi, thereby supporting its secretory function (Delfosse2020Structural).

Overall, OSBP is integral to maintaining lipid equilibrium within cells and orchestrating a range of cellular functions from lipid metabolism to signal transduction.

## Clinical Significance
OSBP (Oxysterol Binding Protein) has been implicated in various diseases due to mutations, altered expression levels, or disruptions in its normal interactions. Mutations in OSBP, such as M446W and V582M, have been identified to confer resistance to antiproliferative compounds known as ORPphilins, which are explored for their potential in cancer therapy. These mutations do not affect the binding to ORPphilins but disrupt necessary protein-protein interactions for their antiproliferative activity (Du2018The). 

Alterations in OSBP expression are linked to several pathological conditions. Overexpression of OSBP can inhibit the processing of amyloid precursor protein (APP) to beta-amyloid, a key player in Alzheimer's disease pathology, while silencing OSBP has the opposite effect, potentially increasing beta-amyloid production (Olkkonen2013Oxysterol-binding). Additionally, OSBP plays a role in viral infections, as evidenced by its interaction with Hepatitis C virus non-structural protein NS5A, influencing the secretion of HCV particles (Olkkonen2013Oxysterol-binding).

Furthermore, OSBP's involvement in cellular sterol metabolism and signaling pathways suggests its potential as a therapeutic target in conditions like cancer and metabolic disorders. The interaction of OSBP with various signaling molecules and pathways, modulated by sterol levels, affects critical cellular functions and disease states, including hepatic triacylglycerol secretion and the stability of nuclear lipogenic SREBP transcription factors (Olkkonen2013Oxysterol-binding).

## Interactions
OSBP (Oxysterol Binding Protein) engages in various physical interactions with proteins, crucial for its function in lipid transport and cellular signaling. Notably, OSBP interacts with vesicle-associated membrane protein-associated protein (VAP) through its FFAT domain, anchoring it to the ER and facilitating lipid regulation and transport (Ridgway2010Oxysterol-Binding; Delfosse2020Structural). Additionally, OSBP's pleckstrin homology (PH) domain binds to phosphatidylinositol phosphates like PI4P, targeting it to the Golgi apparatus, which is essential for its role in cholesterol and PI4P exchange at ER-Golgi contact sites (Ridgway2010Oxysterol-Binding; Delfosse2020Structural).

OSBP also forms complexes with protein phosphatases such as PP2A and the hematopoietic tyrosine phosphatase HePTP. These interactions, facilitated by the cholesterol-bound form of OSBP, lead to the dephosphorylation and inactivation of ERK, a key component of the MAPK signaling pathways (Wang2005OSBP; Ngo2010Functional). Furthermore, OSBP interacts with JAK2, leading to phosphorylation of OSBP and subsequent activation of STAT3, which is involved in the induction of profilin-1, a protein implicated in endothelial dysfunction and atherosclerosis (Kentala2016OSBP-Related). These interactions underline OSBP's pivotal role in linking lipid metabolism with cellular signaling pathways.


## References


[1. (Ridgway2010Oxysterol-Binding) Neale D. Ridgway. Oxysterol-Binding Proteins, pages 159–182. Springer Netherlands, 2010. URL: http://dx.doi.org/10.1007/978-90-481-8622-8_6, doi:10.1007/978-90-481-8622-8_6. (46 citations) 10.1007/978-90-481-8622-8_6](https://doi.org/10.1007/978-90-481-8622-8_6)

[2. (Ngo2010Functional) Mike H. Ngo, Terry R. Colbourne, and Neale D. Ridgway. Functional implications of sterol transport by the oxysterol-binding protein gene family. Biochemical Journal, 429(1):13–24, June 2010. URL: http://dx.doi.org/10.1042/bj20100263, doi:10.1042/bj20100263. (96 citations) 10.1042/bj20100263](https://doi.org/10.1042/bj20100263)

[3. (Du2018The) Ximing Du, Nigel Turner, and Hongyuan Yang. The role of oxysterol-binding protein and its related proteins in cancer. Seminars in Cell & Developmental Biology, 81:149–153, September 2018. URL: http://dx.doi.org/10.1016/j.semcdb.2017.07.017, doi:10.1016/j.semcdb.2017.07.017. (27 citations) 10.1016/j.semcdb.2017.07.017](https://doi.org/10.1016/j.semcdb.2017.07.017)

[4. (Antonny2018The) Bruno Antonny, Joëlle Bigay, and Bruno Mesmin. The oxysterol-binding protein cycle: burning off pi(4)p to transport cholesterol. Annual Review of Biochemistry, 87(1):809–837, June 2018. URL: http://dx.doi.org/10.1146/annurev-biochem-061516-044924, doi:10.1146/annurev-biochem-061516-044924. (113 citations) 10.1146/annurev-biochem-061516-044924](https://doi.org/10.1146/annurev-biochem-061516-044924)

[5. (Kentala2016OSBP-Related) Henriikka Kentala, Marion Weber-Boyvat, and Vesa M. Olkkonen. OSBP-Related Protein Family: Mediators of Lipid Transport and Signaling at Membrane Contact Sites, pages 299–340. Elsevier, 2016. URL: http://dx.doi.org/10.1016/bs.ircmb.2015.09.006, doi:10.1016/bs.ircmb.2015.09.006. (113 citations) 10.1016/bs.ircmb.2015.09.006](https://doi.org/10.1016/bs.ircmb.2015.09.006)

[6. (Lehto2003The) Markku Lehto and Vesa M Olkkonen. The osbp-related proteins: a novel protein family involved in vesicle transport, cellular lipid metabolism, and cell signalling. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1631(1):1–11, February 2003. URL: http://dx.doi.org/10.1016/s1388-1981(02)00364-5, doi:10.1016/s1388-1981(02)00364-5. (144 citations) 10.1016/s1388-1981(02)00364-5](https://doi.org/10.1016/s1388-1981(02)00364-5)

[7. (Pietrangelo2018Bridging) Antonietta Pietrangelo and Neale D. Ridgway. Bridging the molecular and biological functions of the oxysterol-binding protein family. Cellular and Molecular Life Sciences, 75(17):3079–3098, March 2018. URL: http://dx.doi.org/10.1007/s00018-018-2795-y, doi:10.1007/s00018-018-2795-y. (98 citations) 10.1007/s00018-018-2795-y](https://doi.org/10.1007/s00018-018-2795-y)

[8. (Wang2005OSBP) Ping-yuan Wang, Jian Weng, and Richard G. W. Anderson. Osbp is a cholesterol-regulated scaffolding protein in control of erk1/2 activation. Science, 307(5714):1472–1476, March 2005. URL: http://dx.doi.org/10.1126/science.1107710, doi:10.1126/science.1107710. (241 citations) 10.1126/science.1107710](https://doi.org/10.1126/science.1107710)

[9. (Olkkonen2013Oxysterol-binding) Vesa M. Olkkonen and Shiqian Li. Oxysterol-binding proteins: sterol and phosphoinositide sensors coordinating transport, signaling and metabolism. Progress in Lipid Research, 52(4):529–538, October 2013. URL: http://dx.doi.org/10.1016/j.plipres.2013.06.004, doi:10.1016/j.plipres.2013.06.004. (173 citations) 10.1016/j.plipres.2013.06.004](https://doi.org/10.1016/j.plipres.2013.06.004)

[10. (Delfosse2020Structural) Vanessa Delfosse, William Bourguet, and Guillaume Drin. Structural and functional specialization of osbp-related proteins. Contact, 3:251525642094662, January 2020. URL: http://dx.doi.org/10.1177/2515256420946627, doi:10.1177/2515256420946627. (27 citations) 10.1177/2515256420946627](https://doi.org/10.1177/2515256420946627)

[11. (WANG2002Oxysterol-binding-protein) Cheng WANG, Lellean JeBAILEY, and Neale D. RIDGWAY. Oxysterol-binding-protein (osbp)-related protein 4 binds25-hydroxycholesterol and interacts with vimentin intermediate filaments. Biochemical Journal, 361(3):461–472, January 2002. URL: http://dx.doi.org/10.1042/bj3610461, doi:10.1042/bj3610461. (84 citations) 10.1042/bj3610461](https://doi.org/10.1042/bj3610461)

[12. (Laitinen1999Family) Saara Laitinen, Vesa M. Olkkonen, Christian Ehnholm, and Elina Ikonen. Family of human oxysterol binding protein (osbp) homologues: a novel member implicated in brain sterol metabolism. Journal of Lipid Research, 40(12):2204–2211, December 1999. URL: http://dx.doi.org/10.1016/s0022-2275(20)32095-2, doi:10.1016/s0022-2275(20)32095-2. (66 citations) 10.1016/s0022-2275(20)32095-2](https://doi.org/10.1016/s0022-2275(20)32095-2)