Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR
Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR
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DOI：
10.1016/s0960-0760(98)00153-8
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发表时间：
1999-04-01
影响因子：
4.1
通讯作者：
Strauss, JF
中科院分区：
文献类型：
--
作者：
Miller, WL;Strauss, JF
所有类固醇激素合成的第一步和限速步骤是通过线粒体酶P450 SCC将胆固醇转化为胆固醇烯醇酮。促肾上腺皮质激素（ACTH）和促性腺激素等热带激素通过cAMP诱导类固醇生成，其通过两种不同的方式产生细胞内cAMP刺激P450 SCC活性。慢性刺激（小时至天）通过诱导P450 SCC基因转录发生，导致P450 SCC蛋白增加，从而增加类固醇生成能力。急性调节，在几分钟内，发生通过磷酸化的预先存在的星星和新的星星蛋白的快速合成。星星，类固醇生成急性调节蛋白，增加胆固醇流入线粒体，从而调节底物的可用性，无论P450 SCC的量是可用的。在没有星星的情况下，高达14%的最大StAR诱导的类固醇生成水平持续作为StAR非依赖性类固醇生成。先天性类脂质肾上腺增生症是一种常染色体隐性遗传疾病，其中胆固醇转化为双烯醇酮严重受损，导致46，XY遗传男性的女性生殖器，在生命的最初几个月内发生严重失盐危象，但在46，XX女性中正常女性化和周期性阴道出血。脂质CAH曾被认为是由于P450 SCC突变，但事实上纯合子P450 SCC突变不可能存在于人类中，因为它们会抑制胎盘孕酮的产生，导致受影响胎儿的自然流产。脂质CAH是由StAR突变引起的，StAR突变导致肾上腺和性腺中的嗜热带植物诱导的细胞内胆固醇积累。我们的两个打击模型，它认为StAR独立的类固醇生成的持久性和差异的胎儿和出生后的年龄，在睾丸，肾上腺髓质glomerulosa，肾上腺皮质束状体和卵巢的刺激，预测和解释所有的各种临床表现的类脂CAH.星星的结构-功能研究表明，生物活性的关键领域驻留在蛋白质的羧基末端。当N-末端线粒体靶向序列被删除并且产生的N-62星星保留在细胞质中时，它保留了在完整细胞中或在体外添加到分离的线粒体时刺激类固醇生成的能力。这些观察结果表明，星星作用于线粒体外膜，以促进固醇转运到P450 SCC，并且星星输入线粒体终止其作用。圆二色性和傅立叶变换红外光谱的数据表明，突变的星星蛋白在类脂CAH是错误折叠的，这表明中断与另一种蛋白质的相互作用。初步数据表明，星星促进胆固醇从膜上解吸，刺激从线粒体外膜（供体）转移到线粒体内膜（受体）。(C)1999爱思唯尔科技有限公司。保留所有权利。
The first and rate-limiting step in the synthesis of all steroid hormones is the conversion of cholesterol to pregnenolone by the mitochondrial enzyme, P450scc. Tropic hormones such ACTH and gonadotropins induce steroidogenesis via cAMP by elaborating intracellular cAMP which stimulates P450scc activity in two distinct ways. Chronic stimulation (h to days) occurs through the induction of P450scc gene transcription leading to increased P450scc protein and consequent increased steroidogenic capacity. Acute regulation, over minutes, occurs through the phosphorylation of preexisting StAR and the rapid synthesis of new StAR protein. StAR, the steroidogenic acute regulatory protein, increases the flow of cholesterol into mitochondria, thus regulating substrate availability to whatever amount of P450scc is available. In the absence of StAR, up to 14% of maximal StAR-induced level of steroidogenesis persists as StAR-independent steroidogenesis. Congenital lipoid adrenal hyperplasia, an autosomal recessive disorder in which conversion of cholesterol to pregnenolone is severely impaired, results in female genitalia in 46,XY genetic males, variable onset of a severe salt-losing crisis in the first months of life, but normal feminization and cyclical vaginal bleeding in 46,XX females. Lipoid CAH was once thought to be due to P450scc mutations, but in fact homozygous P450scc mutations cannot exist in human beings as they would prohibit placental progesterone production, causing spontaneous abortion of the affected fetus. Lipoid CAH is caused by StAR mutations, which result in tropic hormone-induced intracellular accumulation of cholesterol in the adrenals and gonads. Our two-hit model, which considers the persistence of StAR-independent steroidogenesis and the differences in the fetal and postnatal ages at which the testis, adrenal zona glomerulosa, adrenal zona fasciculata and ovary are stimulated, predicts and explains all of the various clinical manifestations of lipoid CAH.Structure-function studies of StAR show that the critical domains for biological activity reside in the protein's carboxy-terminus. When the N-terminal mitochondrial targeting sequences are deleted and the resulting N-62 StAR remains in the cytoplasm, it retains the ability to stimulate steroidogenesis both in intact cells or when added to isolated mitochondria in vitro. These observations suggest that StAR acts on the outer mitochondrial membrane to promote sterol translocation to P450scc, and that the importation of StAR into mitochondria terminates its action. Data from circular dichroism and Fourier-transform infrared spectroscopy show that the mutant StAR proteins in lipoid CAH are misfolded, suggesting disrupted interaction with another protein. Preliminary data suggest that StAR facilitates cholesterol desorption from membranes, stimulating transfer from the outer mitochondrial (donor) membrane to the inner mitochondrial (acceptor) membrane. (C) 1999 Elsevier Science Ltd. All rights reserved.