Steroidogenic acute regulatory protein (StAR) and the intramitochondrial translocation of cholesterol.
The steroidogenic acute regulatory (StAR) protein regulates the rate limiting step in steroidogenesis, the transport of cholesterol from the outer to the inner mitochondrial membrane. Insight into the structure and function of StAR was attained through molecular genetic studies of congenital lipoid adrenal hyperplasia, a rare disease caused by mutations in the StAR gene. Subsequent functional analysis defined two major domains within the StAR protein, the N-terminal mitochondrial targeting sequence and the C-terminus, which promotes the translocation of cholesterol between the two mitochondrial membranes. Two models of StAR's mechanism of action, (1) stimulation of cholesterol desorption from the outer mitochondrial membrane and (2) an intermembrane shuttle hypothesis, are discussed with respect to the known biochemical and biophysical events associated with the process of steroidogenesis and the structure of StAR. StAR gene expression is regulated primarily at the transcriptional level, and the roles of transcription factors that govern basal and cAMP-dependent StAR expression including SF-1, C/EBP beta, Sp1 and GATA-4 are reviewed.
Christenson
L K
LK
Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, 1355 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA. lchriste@mail.med.upenn.edu
Strauss
J F
JF
D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011284:Pregnenolone / Q000378:metabolism; D017385:Sequence Homology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D000098682:Steroidogenic Acute Regulatory Protein
D002352:Carrier Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C105684:STARD3 protein, human; D000098682:Steroidogenic Acute Regulatory Protein; D011284:Pregnenolone; D002784:Cholesterol