Steroidogenic acute regulatory protein: an update on its regulation and mechanism of action.
Steroidogenic acute regulatory (StAR) protein controls the rate-limiting step in steroidogenesis: the transport of cholesterol from the outer to the inner mitochondrial membrane. Early studies indicated that rate of transcription of the StAR gene is a primary determinant of steroidogenesis. The transcription factors that govern basal and cAMP-dependent StAR expression are reviewed, as are new findings regarding chromatin modifications associated with activation of the StAR promoter. Molecular genetic studies of congenital lipoid adrenal hyperplasia, a rare disease caused by mutations in the StAR gene, and structure-function studies defined two major domains within the StAR protein, the N-terminal mitochondrial targeting sequence and the C-terminal StAR-related lipid transfer (START) domain, which promotes the translocation of cholesterol between the two mitochondrial membranes. Several models of StAR's mechanism of action have been proposed based on a combination of structure/function studies or on the crystal structure of a related START domain. The models-intermembrane shuttle hypothesis, and cholesterol desorption hypothesis-are discussed with respect to the known biochemical and biophysical events associated with steroidogenesis and the structure of StAR.
Christenson
L K
LK
Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia, PA, USA. lchriste@mail.med.upenn.edu
Strauss
J F
JF
D000107:Acetylation; D000312:Adrenal Hyperplasia, Congenital / Q000145:classification / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D002352:Carrier Proteins; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016415:Sequence Alignment; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid; D013256:Steroids / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D000098682:Steroidogenic Acute Regulatory Protein
D002352:Carrier Proteins; D006657:Histones; D008563:Membrane Lipids; D008565:Membrane Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; C105684:STARD3 protein, human; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol