StAR protein

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Steroid Acute Regulator
Steroid Acute Regulator

Available structural data : PDB  1img , 2i93

Properties of human protein
Mass / length primary structure <285 amino acids
Identifier
Gene name STAR
External IDs
Transporter classification
TCDB 9.B.64
designation Cholesterol transporters
Occurrence
Parent taxon Multicellular animals

The StAR protein (abbreviation for Steroidogenic Acute Regulatory Protein ) is a protein that is essential for the transport of cholesterol from the outer membrane of mitochondria to the inner mitochondrial membrane in multicellular animals . This transport determines the rate of steroid hormone biosynthesis and takes place in humans in the gonads , the adrenal cortex , the kidneys and in the male pancreas as well as in the brain. Gender differences in production are evident in the pancreas, which does not express any StAR protein in women.

Mutations in STAR - gene can StAR deficiency and this for life-threatening congenital adrenal hyperplasia lead type. 1

Function of StAR

Targeted attachment to mitochondria

The N-terminus of StAR forms a signal with which StAR binds in a targeted manner to mitochondria. This signal is split off when StAR penetrates the inside of the mitochondrion and StAR is thereby inactivated.

Cholesterol binding domain

The C-terminal part of StAR forms a pocket in which cholesterol can be stored. The genetic removal of this pocket causes an almost complete blockage of the cholesterol import into the inner mitochondrial membrane. This START domain is found in other proteins, MLN64, StarD4, StarD5 and StarD6. Since these proteins lack the target sequence for mitochondria, they are probably not involved in the initiation of steroid formation.

After the binding of StAR to mitochondria, the C-terminal helix is ​​supposed to lift off the cholesterol pocket. This allows cholesterol to be released, which is then made up of other proteins, e.g. B. from the translocator protein (TSPO; known as a benzodiazepine receptor peripheral type (PBR, BZRP) for a long time, but only now assigned to a function) in a pore into the inner mitochondrial membrane. The binding affinity of cholesterol to TSPO is significantly stronger than that to StAR.

Role of TSPO in the activation of StAR through phosphorylation

TSPO is also supposed to bind a PAP7 (also known as protein 3 (ACBD3) containing acyl-coenzyme A binding domain) to the outer mitochondrial membrane, to which in turn a protein kinase A attaches, which phosphorylates StAR and thus significantly accelerates the pregnenolone formation .

Regulation of StAR

The transcription and translation of StAR is controlled by hormones: luteinizing hormone (LH) in the gonads, adrenocorticotrophic hormone (ACTH) in the adrenal gland. The G-protein-coupled membrane receptors (GPCR) for LH or ACTH increase the cAMP concentration, which ultimately leads to StAR expression. By splitting off the mitochondrial target signal and the associated inactivation of StAR, the import of cholesterol into mitochondria can quickly be stopped again if translation does not continue. It has been calculated that around 1.8 molecules of cholesterol are imported per molecule of StAR. This means that the cholesterol import from the translation of StAR is almost stoichiometrically related: per StAR protein formed import of not even two cholesterol molecules.

The activity of StAR in Leydig cells is through phosphorylation by protein kinase A reinforced.

The expression of StAR is regulated in the gonads by gonadotropins . LH is necessary for the expression of StAR in granulosa cells ; it is reduced by TGF-β 1 and increased by prostaglandin E2 . The production of StAR is increased in hepatocellular carcinoma , which leads to increased cholesterol content in the mitochondrial membrane and thus to resistance to chemotherapy .

Individual evidence

  1. ↑ UniProt P49675
  2. ↑ a b c d M.B. Rone, J. Fan, V. Papadopoulos: Cholesterol transport in steroid biosynthesis: Role of protein-protein interactions and implications in disease states . In: Biochimica et Biophysica Acta . tape 1791 , 2009, p. 646-658 .
  3. ↑ A. Morales, F. Vilchis, B. Chávez et al .: Differential expression of steroidogenic factors 1 and 2, cytochrome p450scc, and steroidogenic acute regulatory protein in human pancreas . In: pancreas . tape 37 , no. 2 , August 2008, p. 165-169 , doi : 10.1097 / MPA.0b013e318168dd8c , PMID 18665078 .
  4. ↑ a b T. S. Kostic, NJ Stojkov, MM Janjic, D. Maric, SA Andric: The adaptive response of adult rat Leydig cells to repeated immobilization stress: the role of protein kinase A and steroidogenic acute regulatory protein . In: Stress . tape 11 , no. 5 , 2008, p. 370-380 , doi : 10.1080 / 10253890701822378 , PMID 18800309 .
  5. ↑ RC Tuckey, MJ Headlam, HS Bose, WL Miller: Transfer of cholesterol between phospholipid vesicles mediated by the steroidogenic acute regulatory protein (StAR) . In: J Biol Chem . tape 277 , no. 49 , 2002, pp. 47123-47128 , doi : 10.1074 / jbc.M206965200 .
  6. ↑ T. Sugawara, M. Kiriakidou, JM McAllister, JA Holt, F. Arakane, JF Strauss: Regulation of expression of the steroidogenic acute regulatory protein (StAR) gene: a central role for steroidogenic factor 1 . In: Steroids . tape 62 , no. 1 , January 1997, p. 5-9 , PMID 9029708 .
  7. ↑ X. Zheng, CA Price, Y. Tremblay, JG Lussier, PD Carrière: Role of transforming growth factor-beta1 in gene expression and activity of estradiol and progesterone-generating enzymes in FSH-stimulated bovine granulosa cells . In: Reproduction . tape 136 , no. 4 , October 2008, p. 447-457 , doi : 10.1530 / REP-07-0316 , PMID 18635743 .
  8. ↑ R. Duggavathi, DH Full, C. Mataki include: Liver receptor homolog 1 is essential for ovulation . In: Genes Dev. Band 22 , no. July 14 , 2008, p. 1871–1876 , doi : 10.1101 / gad.472008 , PMID 18628394 , PMC 2492734 (free full text).
  9. ↑ CC Hsu, CW Lu, BM Huang, MH Wu, SJ Tsai: Cyclic adenosine 3 ', 5'-monophosphate response element-binding protein and CCAAT / enhancer-binding protein mediate prostaglandin E2-induced steroidogenic acute regulatory protein expression in endometriotic stromal cells . In: Am. J. Pathol. tape 173 , no. 2 , August 2008, p. 433-441 , doi : 10.2353 / ajpath.2008.080199 , PMID 18583320 , PMC 2475780 (free full text).
  10. ↑ J. Montero, A. Morales, L. Llacuna et al .: Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma . In: Cancer Res . tape 68 , no. 13 , July 2008, p. 5246-5256 , doi : 10.1158 / 0008-5472.CAN-07-6161 , PMID 18593925 .

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