Sterol carrier protein 2: a role in steroid hormone synthesis?
The intracellular movement of cholesterol is an important regulated step in the process of steroidogenesis. However, the molecular mechanisms by which cholesterol is translocated to key organelles, including the mitochondria, remains poorly understood. Lipid transfer proteins may have an important function in this process. One candidate lipid transfer protein is sterol carrier protein 2 (SCP2). This 13.2 kDa protein enhances the movement of cholesterol between vesicles and isolated mitochondria. It also stimulates mitochondrial pregnenolone synthesis. When introduced into intact cells, anti-SCP2 antibodies reduce steroid secretion. Moreover, expression of SCP2 in COS cells engineered to produce progestins increases steroid formation. SCP2 is abundant in steroidogenic glands and the pattern of SCP2 gene expression is consistent with a role for the protein in hormone synthesis: SCP2 transcripts are more prominent in the most steroidogenic compartments of the ovary and tropic hormones that stimulate steroidogenesis increase SCP2 gene expression. Other evidence that suggests that SCP2 plays important roles in cellular function includes a remarkable conservation of primary structure across species. The mechanisms by which SCP2 promotes intracellular sterol movement have not been elucidated. The protein appears to bind sterols and is synthesized with a 20 amino acid N-terminal "pro-" sequence that may serve to target SCP2 to mitochondria. In addition, the C-terminus of SCP2 contains a peroxisome-targeting sequence. SCP2 is derived from a large gene that encodes transcripts that are translated into larger proteins of 30 and 58 kDa. The 58 kDa protein, which has some structural homologies with thiolases, seems to be specifically targeted to peroxisomes whereas SCP2 has a broader subcellular distribution. The significance of the peroxisome association of SCP2 and steroidogenesis has not been disclosed. However, diseases of peroxisome function, including adrenoleukodystrophy and Zellweger syndrome, have notable deficits in steroid and bile acid metabolism, thus linking peroxisomes and steroidogenesis. SCP2 is deficient in fibroblasts of patients with these diseases.
Pfeifer
S M
SM
Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia 19104.
Furth
E E
EE
Ohba
T
T
Chang
Y J
YJ
Rennert
H
H
Sakuragi
N
N
Billheimer
J T
JT
Strauss
J F
JF
D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism; D008928:Mitochondria / Q000378:metabolism; D010940:Plant Proteins; D013256:Steroids / Q000096:biosynthesis*
D002352:Carrier Proteins; D010940:Plant Proteins; D013256:Steroids; C072087:sterol carrier proteins; D002784:Cholesterol