Miller Walter L
Department of Pediatrics, Box 0978, University of California, San Francisco, CA 94122-0978, USA.
Biochim Biophys Acta. 2007 Jun;1771(6):663-76. doi: 10.1016/j.bbalip.2007.02.012. Epub 2007 Mar 6.
Cholesterol is a vital component of cellular membranes, and is the substrate for biosynthesis of steroids, oxysterols and bile acids. The mechanisms directing the intracellular trafficking of this nearly insoluble molecule have received increased attention through the discovery of the steroidogenic acute regulatory protein (StAR) and similar proteins containing StAR-related lipid transfer (START) domains. StAR can transfer cholesterol between synthetic liposomes in vitro, an activity which appears to correspond to the trans-cytoplasmic transport of cholesterol to mitochondria. However, trans-cytoplasmic cholesterol transport in vivo appears to involve the recently-described protein StarD4, which is expressed in most cells. Steroidogenic cells must also move large amounts of cholesterol from the outer mitochondrial membrane to the first steroidogenic enzyme, which lies on the matrix side of the inner membrane; this action requires StAR. Congenital lipoid adrenal hyperplasia, a rare and severe disorder of human steroidogenesis, results from mutations in StAR, providing a StAR knockout of nature that has provided key insights into its activity. Cell biology experiments show that StAR moves large amounts of cholesterol from the outer to inner mitochondrial membrane, but acts exclusively on the outer membrane. Biophysical data show that only the carboxyl-terminal alpha-helix of StAR interacts with the outer membrane. Spectroscopic data and molecular dynamics simulations show that StAR's interactions with protonated phospholipid head groups on the outer mitochondrial membrane induce a conformational change (molten globule transition) needed for StAR's activity. StAR appears to act in concert with the peripheral benzodiazepine receptor, but the precise itinerary of a cholesterol molecule entering the mitochondrion remains unclear.
胆固醇是细胞膜的重要组成部分，也是类固醇、氧化甾醇和胆汁酸生物合成的底物。通过发现类固醇生成急性调节蛋白（StAR）和含有StAR相关脂质转运（START）结构域的类似蛋白，引导这种几乎不溶性分子进行细胞内运输的机制受到了更多关注。StAR可在体外合成脂质体之间转运胆固醇，这一活性似乎与胆固醇跨细胞质转运至线粒体的过程相对应。然而，体内跨细胞质胆固醇转运似乎涉及最近描述的蛋白StarD4，它在大多数细胞中都有表达。类固醇生成细胞还必须将大量胆固醇从线粒体外膜转运至位于内膜基质侧的首个类固醇生成酶；这一过程需要StAR。先天性类脂性肾上腺增生是一种罕见且严重的人类类固醇生成障碍疾病，由StAR基因突变引起，这是一种自然发生的StAR基因敲除现象，为深入了解其活性提供了关键线索。细胞生物学实验表明，StAR可将大量胆固醇从线粒体外膜转运至内膜，但仅作用于外膜。生物物理数据表明，只有StAR的羧基末端α螺旋与外膜相互作用。光谱数据和分子动力学模拟表明，StAR与线粒体外膜上质子化磷脂头部基团的相互作用会诱导其活性所需的构象变化（熔球态转变）。StAR似乎与外周苯二氮䓬受体协同作用，但胆固醇分子进入线粒体的确切路径仍不清楚。
