Structure and lipid transport mechanism of a StAR-related domain

The steroidogenic acute regulatory protein (StAR) regulates acute steroidog enesis in the adrenal cortex and gonads by promoting the translocation of c holesterol to the mitochondrial inner membrane where the first step in ster iod biosynthesis is catalyzed. StAR-related lipid transfer (START) domains occur in proteins involved in lipid transport and metabolism, signal transd uction. and transcriptional regulation. The 2.2 Angstrom resolution crystal structure of the START domain of human MLN64 reported here reveals an alph a/beta fold built around a U-shaped incomplete beta-barrel. The interior of the protein encompasses a 26 x 12 x 11 A hydrophobic tunnel that is large enough to bind a single cholesterol molecule. The StAR and MLN64 START doma ins bind 1 mole of C-14 cholesterol per mole of protein in vitro. Based on the START domain structure and cholesterol binding stoichiometry, it is pro posed that StAR acts by shuttling cholesterol molecules one at a time throu gh the intermembrane space of the mitochondrion.