Steroidogenic acute regulatory protein: Wikis

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steroidogenic acute regulatory protein
Identifiers
Symbol StAR
Entrez 6770
HUGO 11359
OMIM 600617
RefSeq NM_000349
UniProt P49675
Other data
Locus Chr. 8 p11.2

The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.

Contents

Function

Cholesterol needs to be transferred from the outer mitochondrial membrane to the inner membrane where cytochrome P450scc enzyme is located to split off the cholesterol side chain, which is the first enzymatic step in all steroid synthesis. The aqueous phase between these two membranes cannot be crossed by the lipophilic cholesterol, unless certain proteins assist in this process. A number of proteins have historically been proposed to facilitate this transfer including: sterol carrier protein 2 (SCP2), steroidogenic activator polypeptide (SAP), peripheral benzodiazepine receptor (PBR), and StAR. It is now clear that this process is primarily mediated by the action of StAR.

The mechanism by which StAR causes cholesterol movement remains unclear as it appears to act from the outside of the mitochondria and its entry into the mitochondria ends its function. Various hypotheses have been advanced. Some involve StAR transferring cholesterol itself like a shuttle. [1][2] While StAR may bind cholesterol itself[3], the exorbitant number of cholesterol molecules that the protein transfers would indicate that it would have to act as a cholesterol channel instead of a shuttle. Another notion is that it causes cholesterol to be kicked out of the outer membrane to the inner (cholesterol desorption).[4] StAR may also promote the formation of contact sites between the outer and inner mitochondrial membranes to allow cholesterol influx. Another suggests that StAR acts in conjunction with PBR, causing the movement of Cl- out of the mitochondria to facilitate contact site formation. However, evidence for an interaction between StAR and PBR remains elusive.

Structure

In humans, the gene for StAR is located on chromosome 8p11.2 and the protein has 285 amino acids. The signal sequence of StAR that targets it to the mitochondria is clipped off in two steps with import into the mitochondria. Phosphorylation at the serine at position 195 increases its activity.[5]

The domain of StAR important for promoting cholesterol transfer is the StAR-related transfer domain (START domain). StAR is the prototypic member of the START domain family of proteins and is thus also known as STARD1 for "START domain-containing protein 1".[6] It is hypothesized that the START domain forms a pocket in StAR that binds single cholesterol molecules for delivery to P450scc.

The closest homolog to StAR is MLN64.[7]

Production

StAR is a mitochondrial protein that is rapidly synthesized in response to stimulation of the cell to produce steroid. Hormones that stimulate its production depend on the cell type and include luteinizing hormone (LH), ACTH and angiotensin II.

At the cellular level, StAR is synthesized typically in response to activation of the cAMP second messenger system, although other systems can be involved even independently of cAMP.[8]

StAR has thus far been found in all tissues that can produce steroids, including the adrenal cortex, the gonads, the brain and placenta.[9] One known exception is the human placenta.

Alcohol suppresses StAR activity.[10]

Pathology

Mutations in the gene for StAR cause lipoid congenital adrenal hyperplasia, in which patients produce little steroid and can die shortly after birth.[9] All known mutations disrupt StAR function by altering its START domain. In the case of StAR mutation, the phenotype does not present until birth since human placental steroidogenesis is independent of StAR.

At the cellular level, the lack of StAR results in a pathologic accumulation of lipid within cells, especially noticeable in the adrenal cortex as seen in the mouse model. The testes is modestly affected. Early in life, the ovary is spared as it does not express StAR until puberty. After puberty, lipid accumulations and hallmarks of ovarian failure are noted.

StAR-Independent Steroidogenesis

While loss of functional StAR in the human and the mouse catastrophically reduces steroid production, it does not eliminate all of it, indicating the existence of StAR-independent pathways for steroid generation. Aside from the human placenta, these pathways are considered minor for endocrine production.

It is unclear what factors catalyze StAR-independent steroidogenesis. Candidates include oxysterols which can be freely converted to steroid[11] and the ubiquitous MLN64.

References

  1. ^ Kallen CB, Billheimer JT, Summers SA, Stayrook SE, Lewis M, Strauss III JF (October 1998). "Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein". J. Biol. Chem. 273 (41): 26285–8. PMID 9756854.  
  2. ^ Bose HS, Whittal RM, Baldwin MA, Miller WL (June 1999). "The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7250–5. PMID 10377400.  
  3. ^ Roostaee A, Barbar E, Lehoux JG, Lavigne P (June 2008). "Cholesterol binding is a prerequisite for the activity of the steroidogenic acute regulatory protein (StAR)". Biochem. J. 412 (3): 553–62. PMID 18341481.  
  4. ^ Christenson LK, Strauss III JF (2001). "Steroidogenic acute regulatory protein: an update on its regulation and mechanism of action". Arch. Med. Res. 32 (6): 576–86. PMID 11750733.  
  5. ^ Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM, Strauss JF (December 1997). "Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity". J. Biol. Chem. 272 (51): 32656–62. doi:10.1074/jbc.272.51.32656. PMID 9405483.  
  6. ^ Ponting CP, Aravind L (April 1999). "START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins". Trends Biochem. Sci. 24 (4): 130–2. doi:10.1016/S0968-0004(99)01362-6. PMID 10322415.  
  7. ^ Alpy F, Tomasetto C (June 2006). "MLN64 and MENTHO, two mediators of endosomal cholesterol transport". Biochem. Soc. Trans. 34 (Pt 3): 343–5. doi:10.1042/BST0340343. PMID 16709157.  
  8. ^ Stocco DM, Wang X, Jo Y, Manna PR. Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. Mol Endocrinol. 2005 Nov;19(11):2647-59. PMID 15831519
  9. ^ a b Bhangoo A, Anhalt H, Ten S, King SR (March 2006). "Phenotypic variations in lipoid congenital adrenal hyperplasia". Pediatr Endocrinol Rev 3 (3): 258–71. PMID 16639391.  
  10. ^ Srivastava VK, Vijayan E, Hiney JK, Dees WL (October 2005). "Effect of ethanol on follicle stimulating hormone-induced steroidogenic acute regulatory protein (StAR) in cultured rat granulosa cells". Alcohol 37 (2): 105–11. doi:10.1016/j.alcohol.2006.01.001. PMID 16584974.  
  11. ^ Hutson JC (January 2006). "Physiologic interactions between macrophages and Leydig cells". Exp. Biol. Med. (Maywood) 231 (1): 1–7. PMID 16380639. http://www.ebmonline.org/cgi/content/abstract/231/1/1.  

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