Steroidogenic Acute Regulatory Protein (StAR), also known as STARD1, is a crucial transport protein that regulates cholesterol transfer within the mitochondria. This process is the rate-limiting step in the production of steroid hormones. StAR is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis, and various cell types in the adrenal cortex .
StAR is synthesized as a precursor containing a mitochondrial localization sequence and a sterol-binding domain. The protein significantly accelerates cholesterol transport to the inner mitochondrial membrane, where it is converted by cytochrome P450scc (CYP11A1) into pregnenolone, the common precursor of all steroid hormones . The gene for StAR is located on chromosome 8p11.23, and the protein consists of 285 amino acids .
The domain of StAR important for promoting cholesterol transfer is the StAR-related transfer domain (START domain). StAR is the prototypic member of the START domain family of proteins and is thus also known as STARD1 for "START domain-containing protein 1" .
The exact mechanism by which StAR facilitates cholesterol movement remains unclear. It appears to act from the outside of the mitochondria, and its entry into the mitochondria ends its function. Various hypotheses have been proposed, including the idea that StAR transfers cholesterol itself like a shuttle or acts as a cholesterol channel . Another notion is that it causes cholesterol to be kicked out of the outer membrane to the inner membrane (cholesterol desorption) .
The expression of the StAR protein is predominantly regulated by cAMP-dependent mechanisms in the adrenal and gonads . ACTH interaction with specific membrane receptors leads to the activation of coupled G proteins, with subsequent stimulation of membrane-associated adenylyl cyclase catalyzing cAMP formation. cAMP-activated PKA hence phosphorylates multiple transcription factors, whose concerted action and interaction with different cis-regulatory elements direct StAR and steroidogenic gene expression .
StAR plays a major role in supplying mitochondria with cholesterol, and its dysfunction can lead to various hereditary diseases. For instance, mutations in the StAR gene can cause lipoid congenital adrenal hyperplasia (LCAH), a severe disorder of steroid hormone biosynthesis . Understanding the structure, functioning, and regulation of StAR is crucial for developing therapeutic strategies for such conditions.