Providing progesterone for pregnancy: control of cholesterol flux to the side-chain cleavage system.
Progesterone, which is required to support human gestation, is derived initially from the corpus luteum and subsequently from the placenta. The rate-limiting step in progesterone synthesis is the delivery of cholesterol to the mitochondrial cholesterol side-chain cleavage system. The steroidogenic acute regulatory protein (StAR) mediates this process in the corpus luteum, whereas in the placenta, which does not express StAR, a StAR homologue, MLN64, may accomplish this function. StAR expression is regulated in the ovary at the transcriptional level by a cAMP-activated signal transduction system and StAR activity is also increased acutely by protein kinase A-mediated phosphorylation. These long-term (transcriptional) and short-term (post-translational, that is, phosphorylation) mechanisms govern luteal steroidogenic activity. The StAR protein has two key functional domains. The StAR C-terminal domain increases cholesterol movement to cytochrome P450scc by promoting sterol desorption from the sterol-rich outer mitochondrial membrane, driving it to the relatively sterol-poor inner membrane. The N-terminal domain mitochondrial targeting sequence directs the StAR protein to the mitochondria.
Strauss
J F
JF
Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia 19104-6142, USA.
Christenson
L K
LK
Devoto
L
L
Martinez
F
F
D002352:Carrier Proteins; D002784:Cholesterol / Q000378:metabolism*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism*; D003338:Corpus Luteum / Q000378:metabolism*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D000098682:Steroidogenic Acute Regulatory Protein
D002352:Carrier Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C105684:STARD3 protein, human; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D002784:Cholesterol; D002786:Cholesterol Side-Chain Cleavage Enzyme