Steroidogenic acute regulatory protein

protein
Name=steroidogenic acute regulatory proteinth
caption=


width=
HGNCid=11359
Symbol=StAR
AltSymbols=
EntrezGene=6770
OMIM=600617
RefSeq=NM_000349
UniProt=P49675
PDB=
ECnumber=
Chromosome=8
Arm=p
Band=11.2
LocusSupplementaryData=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.

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 on PBR causing the movement of Cl^- out of the mitochondria, bringing the outer and inner mitochondrial membranes together.

tructure

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. [Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM, Strauss III JF. Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. J Biol Chem. 1997 Dec 19;272(51):32656-62. PMID 9405483]

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. [ Ponting CP, Aravind L. START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins. Trends Biochem Sci. 1999 Apr;24(4):130-2. PMID 10322415] 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. [Alpy F, Tomasetto C. MLN64 and MENTHO, two mediators of endosomal cholesterol transport. Biochem Soc Trans. 2006 Jun;34(Pt 3):343-5. PMID 16709157]

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.

StAR has thus far been found in all tissues that can produce steroids, including the adrenal cortex, the gonads, the brain and placenta. [Bhangoo A, Anhalt H, Ten S, King SR. Phenotypic variations in lipoid congenital adrenal hyperplasia. Pediatr Endocrinol Rev. 2006 Mar;3(3):258-71. PMID 16639391] One known exception is the human placenta.

Alcohol suppresses StAR activity. [Srivastava VK, Vijayan E, Hiney JK, Dees WL. Effect of ethanol on follicle stimulating hormone-induced steroidogenic acute regulatory protein (StAR) in cultured rat granulosa cells. Alcohol. 2005 Oct;37(2):105-11. PMID 16584974]

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. [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]

Pathology

Mutations in the gene for StAR cause lipoid congenital adrenal hyperplasia, in which patients produce little steroid and can die shortly after birth. [Bhangoo A, Anhalt H, Ten S, King SR. Phenotypic variations in lipoid congenital adrenal hyperplasia. Pediatr Endocrinol Rev. 2006 Mar;3(3):258-71. PMID 16639391] All known mutations disrupt StAR function by altering its START domain. In the case of StAR mutation, phenotype does not present until birth as placental steroidogenesis relies on MLN64, a homologue 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.

tAR-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 [Hutson JC. Physiologic interactions between macrophages and Leydig cells. Exp Biol Med (Maywood). 2006 Jan;231(1):1-7. PMID 16380639] and the ubiquitous MLN64.

References

External links

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