Steroidogenic acute regulatory protein 5350008 205864601 2008-04-15T20:16:43Z 68.198.54.79 {{protein |Name=steroidogenic acute regulatory proteinth |caption= |image= |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 [[mitochondria]]l 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<sup>-</sup> out of the mitochondria, bringing the outer and inner mitochondrial membranes together. ==Structure== In humans, the gene for StAR is located on [[chromosome 8]]p11.2 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.<ref>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</ref> 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.<ref> 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</ref> It is hypothesized that the START domain forms a pocket in StAR that binds single [[cholesterol]] molecules for delivery to [[P450scc]]. The closest [[homology (biology)|homolog]] to StAR is [[MLN64]].<ref>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</ref> ==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|angiotensin II]]. StAR has thus far been found in all tissues that can produce steroids, including the [[adrenal]] cortex, the [[gonad]]s, the [[brain]] and [[placenta]].<ref>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</ref> One known exception is the human placenta. [[Ethanol|Alcohol]] suppresses StAR activity.<ref>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</ref> 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]].<ref>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</ref> ==Pathology== [[Mutations]] in the gene for StAR cause [[lipoid congenital adrenal hyperplasia]], in which patients produce little steroid and can die shortly after birth.<ref>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</ref> 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. ==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<ref>Hutson JC. Physiologic interactions between macrophages and Leydig cells. Exp Biol Med (Maywood). 2006 Jan;231(1):1-7. PMID 16380639</ref> and the ubiquitous [[MLN64]]. ==References== <references/> ==External links== * {{UMichOPM|families|superfamily|147}} * {{MeshName|steroidogenic+acute+regulatory+protein}} [[Category:steroids]] [[Category:Water-soluble transporters]] [[Category:Peripheral membrane proteins]]