Steroidogenic Acute Regulatory Protein (StAR) Is A Sterol Transfer Protein

Abstract

Steroidogenic acute regulatory protein (StAR) plays a critical role in steroidogenesis by enhancing the delivery of substrate cholesterol from the outer mitochondrial membrane to the cholesterol side chain cleavage enzyme system on the inner membrane. A recombinant StAR protein lacking the first N-terminal 62 amino acid residues that includes the mitochondrial targeting sequence was shown to stimulate the transfer of cholesterol and ␤-sitosterol from liposomes to heat-treated mitochondria in a dose-, time-, and temperature-dependent manner. A recombinant mutant StAR protein that cannot stimulate steroidogenesis by isolated mitochondria did not promote sterol transfer. Unlike the more promiscuous lipid transfer protein, sterol carrier protein 2 (SCP 2 ), StAR did not stimulate phosphatidylcholine transfer in our assay system. The recombinant StAR protein increased cholesterol transfer to heattreated microsomes as well as to heat-and trypsintreated mitochondria. These observations demonstrate that StAR has sterol transfer activity, which may reflect an ability to enhance desorption of cholesterol from sterol-rich donor membranes. We suggest that the ability of StAR to promote sterol transfer explains its steroidogenic activity.

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…StAR is synthesized as a short-lived cytoplasmic 37-kDa protein with a mitochondrial leader peptide that is cleaved upon mitochondrial import to yield the long-lived intramitochondrial 30-kDa form [58]. It is now wellestablished that StAR functions as a sterol transfer protein [70], binds cholesterol [71,72], mediates the acute steroidogenic response by moving cholesterol from the outer to the inner mitochondrial membrane [73], acts on the outer mitochondrial membrane [73][74][75], and requires the structural change previously described as a pH-dependent molten globule [76]. StAR is also a prototype of a family of proteins that contain START (StAR-related lipid transfer) domains (StarD proteins) [77], of which StarD3/MLN64, StarD4, StarD5 and StarD6 exhibit steroidogenic potential [78,79].…”

Serum estrogen level and lipid profile in Gall stone and Gallbladder cancer: a case control study

“…Cholesterol is taken up by steroidogenic cells, stored, and moved in to the site of steroid synthesis 20 . The different steroids are formed by reduction in the number of carbon atoms from 27 to 18 21 .…”

Targeted Mutation of the MLN64 START Domain Causes Only Modest Alterations in Cellular Sterol Metabolism

“…Recent findings indicate that a family of proteins related to the steroidogenic acute regulatory protein (StAR) 1 perform critical functions in moving lipids within cells (1)(2)(3)(4). StAR, the prototype of the family, promotes the translocation of cholesterol from the outer to the inner mitochondrial membrane and cholesterol side-chain cleavage enzyme in steroidogenic cells (1,5,6). Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia, a cholesterol storage disorder in which synthesis of all gonadal and adrenal cortical steroid hormones is severely impaired; the cholesterol that is not efficiently moved into the mitochondria accumulates in cytoplasmic lipid droplets (7,8).…”

“…Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia, a cholesterol storage disorder in which synthesis of all gonadal and adrenal cortical steroid hormones is severely impaired; the cholesterol that is not efficiently moved into the mitochondria accumulates in cytoplasmic lipid droplets (7,8). The C terminus of StAR possesses sterol transfer activity, and it has been named the StARrelated lipid transfer (START) domain (2,6,9). It consists of a 210-amino acid residue sequence that forms a compact ␣/␤ structure, a helix-grip fold, with a hydrophobic tunnel that can accommodate a sterol molecule (2, 10 -12).…”