STEROL CARRIER PROTEIN-2 - A ROLE IN STEROID-HORMONE SYNTHESIS

The intracellular movement of cholesterol is an important regulated st ep in the process of steroidogenesis. However, the molecular mechanism s by which cholesterol is translocated to key organelles, including th e mitochondria, remains poorly understood. Lipid transfer proteins may have an important function in this process. One candidate lipid trans fer protein is sterol carrier protein 2 (SCP2). This 13.2 kDa protein enhances the movement of cholesterol between vesicles and isolated mit ochondria. It also stimulates mitochondrial pregnenolone synthesis. Wh en introduced into intact cells, anti-SCP2 antibodies reduce steroid s ecretion. Moreover, expression of SCP2 in COS cells engineered to prod uce progestins increases steroid formation. SCP2 is abundant in steroi dogenic glands and the pattern of SCP2 gene expression is consistent w ith 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 exp ression. Other evidence that suggests that SCP2 plays important roles in cellular function includes a remarkable conservation of primary str ucture across species. The mechanisms by which SCP2 promotes intracell ular 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. SCP 2 is derived from a large gene that encodes transcripts that are trans lated into larger proteins of 30 and 58 kDa. The 58 kDa protein, which has some structural homologies with thiolases, seems to be specifical ly targeted to peroxisomes whereas SCP2 has a broader subcellular dist ribution. The significance of the peroxisome association of SCP2 and s teroidogenesis 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 pe roxisomes and steroidogenesis. SCP2 is deficient in fibroblasts of pat ients with these diseases.