Gene structure, intracellular localization, and functional roles of sterolcarrier protein-2

Since its, discovery three decades ago, sterol carrier protein-2 (SCP-2) ha s remained a fascinating protein whose physiological function in lipid meta bolism remains an enigma. Its multiple proposed functions arise from its, c omplex gene structure, post-translational processing, intracellular localiz ation, and ligand specificity. The SCP-2 gene has two initiation sites codi ng for proteins that share a common 13 kDa SCP2 C-terminus: (1) One site co des for 58 kDa SCP-x which is partially post-translationally cleaved to 13 kDa, SCP-2 and a 45 kDa protein. (2) A second site codes for 15 kDa pro-SCP -2 which is completely posttranslationally cleaved to 13 kDa SCP-2. Very ti ttle is yet known regarding how the relative proportions of the two transcr ipts are regulated. Although all three proteins contain a C-terminal SKL pe roxisomal targeting sequence, it is unclear why all three proteins are not exclusively localized in peroxisomes. However, the recent demonstration tha t the SCP-2 N-terminal presequence in pro-SCP-2 dramatically modulated the intracellular targeting coded by the C-terminal peroxisomal targeting seque nce may account for the observation that as, much as half of total SCP-2 is localized outside the peroxisome. The tertiary and secondary structure of the 13 kDa SCR-2, but not that of 15 kDa pro-SCP-2 and 58 kDa SCP-x, are no w resolved. Increasing evidence suggests that the 58 kDa SCP-x and 45 kDa p roteins are peroxisomal 3-ketoacyl-CoA-thiolases involved in the oxidation of branched chain fatty acids. Since 15 kDa pro-SCP-2 is post-translational ly completely cleaved to 13 kDa SCP-2, relatively little attention has been focused on this protein. Finally, although the 13 kDa SCP-2 is the most st udied of these proteins, because it exhibits diversity of its ligand partne rs (fatty acids, fatty acyl CoAs, cholesterol, phospholipids), new potentia l physiological function(s) are still being proposed and questions regardin g potential compensation by other proteins with overlapping specificity are only beginning to be resolved. (C) 2001 Elsevier Science Ltd. All rights-r eserved.