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词条 OSBP
释义

  1. Function

  2. Mechanism of action

  3. Regulation

  4. Isoforms

  5. References

  6. Further reading

{{Infobox_gene}}Oxysterol-binding protein 1 is a protein that in humans is encoded by the OSBP gene.[1]

Function

Oxysterol-binding protein (OSBP) is an intracellular protein that was identified as a cytosolic 25-hydroxycholesterol-binding protein.[2] OSBP is a lipid transfer protein that controls cholesterol/PI4P exchange at ER-Golgi membrane contact sites.[3] 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.[3] OSBP plays also a role as a sterol-regulated scaffolding protein for several cytosolic reactions including the phosphorylation of ERK 1/2.[4]

It has been shown that expression and maturation of SREBP-1c is controlled by OSBP.[5] SREBP-1c is a major transcription factor for hepatic lipogenesis (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.[4] OSBP also acts as a sterol-dependant scaffold for the JAK2 and STAT3 proteins.[6]

Mechanism of action

OSBP is a multi-domain protein consisting of an N-terminal pleckstrin homology (PH) domain, a central FFAT motif (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(-GTP), whereas the FFAT motif binds the type II ER membrane protein VAP-A.[7][8] OSBP bridges the Golgi and the ER by establishing contacts with all of these determinants simultaneously.[3]

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).[3] 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).[2][9] Several proteins involved in cholesterol homeostasis, such as INSIG-1 or ACAT, also bind 25-OH.[10] 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.[2] 25-OH acts as an inhibitor of sterol transport mediated by OSBP in vitro.[3]

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.[11] 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.[12]

References

1. ^{{cite web | title = Entrez Gene: OSBP oxysterol binding protein| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5007| accessdate = }}
2. ^1 2 {{cite journal | vauthors = Ridgway ND, Dawson PA, Ho YK, Brown MS, Goldstein JL | title = Translocation of oxysterol binding protein to Golgi apparatus triggered by ligand binding | journal = J. Cell Biol. | volume = 116 | issue = 2 | pages = 307–19 |date=January 1992 | pmid = 1730758 | pmc = 2289278 | doi = 10.1083/jcb.116.2.307| url = }}
3. ^1 2 3 4 {{cite journal | vauthors = Mesmin B, Bigay J, Moser von Filseck J, Lacas-Gervais S, Drin G, Antonny B | title = A Four-Step Cycle Driven by PI(4)P Hydrolysis Directs Sterol/PI(4)P Exchange by the ER-Golgi Tether OSBP | journal = Cell | volume = 155 | issue = 4 | pages = 830–43 |date=November 2013 | pmid = 24209621 | doi = 10.1016/j.cell.2013.09.056 }}
4. ^1 {{cite journal | vauthors = Wang PY, Weng J, Anderson RG | title = OSBP is a cholesterol-regulated scaffolding protein in control of ERK 1/2 activation | journal = Science | volume = 307 | issue = 5714 | pages = 1472–6 |date=March 2005 | pmid = 15746430 | doi = 10.1126/science.1107710 }}
5. ^{{cite journal | vauthors = Yan D, Lehto M, Rasilainen L, Metso J, Ehnholm C, Ylä-Herttuala S, Jauhiainen M, Olkkonen VM | title = Oxysterol binding protein induces upregulation of SREBP-1c and enhances hepatic lipogenesis | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 27 | issue = 5 | pages = 1108–14 |date=May 2007 | pmid = 17303778 | doi = 10.1161/ATVBAHA.106.138545 }}
6. ^{{cite journal | vauthors = Romeo GR, Kazlauskas A | title = Oxysterol and diabetes activate STAT3 and control endothelial expression of profilin-1 via OSBP1 | journal = J. Biol. Chem. | volume = 283 | issue = 15 | pages = 9595–605 |date=April 2008 | pmid = 18230613 | doi = 10.1074/jbc.M710092200 }}
7. ^{{cite journal | author = Levine T | title = Short-range intracellular trafficking of small molecules across endoplasmic reticulum junctions | journal = Trends Cell Biol. | volume = 14 | issue = 9 | pages = 483–90 |date=September 2004 | pmid = 15350976 | doi = 10.1016/j.tcb.2004.07.017 }}
8. ^{{cite journal | vauthors = Wyles JP, McMaster CR, Ridgway ND | title = Vesicle-associated membrane protein-associated protein-A (VAP-A) interacts with the oxysterol-binding protein to modify export from the endoplasmic reticulum | journal = J. Biol. Chem. | volume = 277 | issue = 33 | pages = 29908–18 |date=August 2002 | pmid = 12023275 | doi = 10.1074/jbc.M201191200 | url = }}
9. ^{{cite journal | vauthors = Nhek S, Ngo M, Yang X, Ng MM, Field SJ, Asara JM, Ridgway ND, Toker A | title = Regulation of oxysterol-binding protein Golgi localization through protein kinase D-mediated phosphorylation | journal = Mol. Biol. Cell | volume = 21 | issue = 13 | pages = 2327–37 |date=July 2010 | pmid = 20444975 | pmc = 2893995 | doi = 10.1091/mbc.E10-02-0090 }}
10. ^{{cite journal | vauthors = Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS, Goldstein JL | title = Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 16 | pages = 6511–8 |date=April 2007 | pmid = 17428920 | pmc = 1851665 | doi = 10.1073/pnas.0700899104 }}
11. ^{{cite journal | vauthors = Im YJ, Raychaudhuri S, Prinz WA, Hurley JH | title = Structural mechanism for sterol sensing and transport by OSBP-related proteins | journal = Nature | volume = 437 | issue = 7055 | pages = 154–8 |date=September 2005 | pmid = 16136145 | pmc = 1431608 | doi = 10.1038/nature03923 }}
12. ^{{cite journal | vauthors = de Saint-Jean M, Delfosse V, Douguet D, Chicanne G, Payrastre B, Bourguet W, Antonny B, Drin G | title = Osh4p exchanges sterols for phosphatidylinositol 4-phosphate between lipid bilayers | journal = J. Cell Biol. | volume = 195 | issue = 6 | pages = 965–78 |date=December 2011 | pmid = 22162133 | pmc = 3241724 | doi = 10.1083/jcb.201104062 }}

Further reading

{{refbegin|35em}}
  • {{cite journal | vauthors = Levanon D, Hsieh CL, Francke U, Dawson PA, Ridgway ND, Brown MS, Goldstein JL | title = cDNA cloning of human oxysterol-binding protein and localization of the gene to human chromosome 11 and mouse chromosome 19 | journal = Genomics | volume = 7 | issue = 1 | pages = 65–74 |date=May 1990 | pmid = 1970801 | doi = 10.1016/0888-7543(90)90519-Z }}
  • {{cite journal | vauthors = Laitinen S, Olkkonen VM, Ehnholm C, Ikonen E | title = Family of human oxysterol binding protein (OSBP) homologues. A novel member implicated in brain sterol metabolism | journal = J. Lipid Res. | volume = 40 | issue = 12 | pages = 2204–11 |date=December 1999 | pmid = 10588946 | doi = }}
  • {{cite journal | vauthors = Moreira EF, Jaworski C, Li A, Rodriguez IR | title = Molecular and biochemical characterization of a novel oxysterol-binding protein (OSBP2) highly expressed in retina | journal = J. Biol. Chem. | volume = 276 | issue = 21 | pages = 18570–8 |date=May 2001 | pmid = 11278871 | doi = 10.1074/jbc.M011259200 }}
  • {{cite journal | vauthors = Jaworski CJ, Moreira E, Li A, Lee R, Rodriguez IR | title = A family of 12 human genes containing oxysterol-binding domains | journal = Genomics | volume = 78 | issue = 3 | pages = 185–96 |date=December 2001 | pmid = 11735225 | doi = 10.1006/geno.2001.6663 }}
  • {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 33 | pages = 12130–5 |date=August 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 }}
  • {{cite journal | vauthors = Perry RJ, Ridgway ND | title = Oxysterol-binding protein and vesicle-associated membrane protein-associated protein are required for sterol-dependent activation of the ceramide transport protein | journal = Mol. Biol. Cell | volume = 17 | issue = 6 | pages = 2604–16 |date=June 2006 | pmid = 16571669 | pmc = 1474796 | doi = 10.1091/mbc.E06-01-0060 }}
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