StAR-related transfer domain

START (StAR-related lipid-transfer) is a lipid-binding domain in StAR, HD-ZIP and signalling proteins. The archetypical domain is found in StAR (Steroidogenic acute regulatory protein), a mitochondrial protein that is synthesized in steroid-producing cells like Leydig cells in response to a hormone such as luteinising hormone. Expression of the protein in the absence of hormone stimulation is sufficient to induce steroid production, suggesting that this protein is required in the acute regulation of steroidogenesis. Fifteen START-domain-containing proteins (termed STARD1 through STARD15) have been identified in vertebrates. These proteins can be further subdivided into the cholesterol/oxysterol binding subfamilies StarD1/D3 and StarD4 which includes StarD5 and 6, the phospholipid/sphingolipid binding StarD2 subfamily consisting of StarD2, 7, 10 and 11, the SAM-RhoGAP-START subfamily composed of STARD8, 12 and 13 which contain the START domain plus Rho-GTPase signaling activity, Acyl-CoA thioesterase subfamily made up of StarD14 and 15 who possess the START domain and thioesterase activity, and StarD9 whose activity remains unknown.

Thousands of proteins containing at least one START domain have been determined in invertebrates, bacteria and plants to form a larger superfamily, variously known as START, Bet v1-like or SRPBCC (START/RHOalphaC/PITP/Bet v1/CoxG/CalC) domain proteins, all of which bind hydrophobic ligands. Representatives of the START domain family have been shown to bind different substances or ligands such as sterols (e.g., StAR or STARD1) and lipids like phosphatidylcholine (phosphatidylcholine transfer protein, also called PCTP or STARD2) and have enzymatic activities. Ligand binding by the START domain can also regulate the activities of other domains that co-occur with the START domain in multidomain proteins such as RhoGAP domain, the homeodomain, and the thioesterase domain.

The crystal structure of START domain of human MLN64 shows an alpha/beta fold built around an U-shaped incomplete beta-barrel. Most importantly, the interior of the protein encompasses a 26 x 12 x 11 Angstroms hydrophobic tunnel that is apparently large enough to bind a single cholesterol molecule. The START domain structure revealed an unexpected similarity to that of the birch pollen allergen Bet v 1 and to bacterial polyketide cyclases/aromatases.

Human proteins containing this domain
STAR (STARD1);     PCTP (STARD2);  MLN64 (STARD3);    STARD4;    STARD5;    STARD6;    STARD7;    STARD8 (DLC-3); STARD9;   STARD10; COL4A3BP (STARD11);  DLC1 (STARD12); STARD13 (DLC-2);     ACOT11 (STARD14);    ACOT12 (STARD15);