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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA
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Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA

机译：巨细胞病毒蛋白vMIA抑制Bax的结构机制

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摘要

The human protein Bax sits at a critical regulatory junction of apoptosis, or programmed cell death. Bax exists in equilibrium between cytosolic and mitochondria-associated forms that shifts toward the latter when Bax is activated by proapoptotic proteins. Activated Bax changes conformation, inserts into the mitochon-drial outer membrane (MOM), oligomerizes, and induces MOM permeabilization, causing the release of cytochrome c, which effectively commits the cell to die. Because apoptosis is also a basic defense mechanism agajnst invading pathogens, many viruses have developed counteractive measures. Such is the case of human cytomegalovirus, the replication of which hinges on vMIA (viral mitochondria-localized inhibitor of apoptosis), a virus-encoded protein with a unique, albeit poorly understood antiapoptotic activity by which it binds and recruits Bax to mitochondria. Here we show, via the structure determination of the complex between Bax and a peptide comprising vMIA's Bax-binding domain, that vMIA contacts Bax at a previously unknown regulatory site. Notably, using full-length vMIA, the structure is independently confirmed by assays in human cells that measure Bax subcellular localization and cytochrome c release. Mutants that disrupt key intermolecular interactions disfavor vMIA's mitochondrial recruitment of Bax, and increase cytochrome c release upon apoptosis induction. In a more stringent test, an engineered binding interface that achieves wild-type-like charge complementarity, although in a reversed fashion, recovers wild-type behavior. The structure suggests that by stabilizing key elements in Bax needed to unravel for its MOM insertion and oligomerization, vMIA prevents these important steps in apoptosis.
机译：人类蛋白质Bax处于凋亡或程序性细胞死亡的关键调节连接点。 Bax存在于胞质和线粒体相关形式之间的平衡状态，当Bax被促凋亡蛋白激活时，Bax向后者转变。活化的Bax改变构象，插入线粒体-干膜外膜（MOM），寡聚并诱导MOM透化，导致细胞色素c释放，从而有效地使细胞死亡。由于细胞凋亡也是抵御病原体的基本防御机制，因此许多病毒已制定了应对措施。人类巨细胞病毒就是这种情况，其复制取决于vMIA（病毒线粒体定位的凋亡抑制剂），这种病毒编码的蛋白具有独特的抗凋亡活性，尽管人们对其了解甚少，但其结合并招募Bax到线粒体上。在这里，我们通过结构确定Bax与包含vMIA的Bax结合域的肽之间的复合物，表明vMIA在以前未知的调控位点与Bax接触。值得注意的是，使用全长vMIA，该结构可通过人体细胞中测定Bax亚细胞定位和细胞色素c释放的测定独立确认。破坏关键分子间相互作用的突变体不利于vMIA的线粒体Bax募集，并在凋亡诱导后增加细胞色素c的释放。在更严格的测试中，工程化的结合界面可实现类似野生型的电荷互补性，尽管以相反的方式可以恢复野生型的行为。该结构表明，通过稳定Bax中MOM插入和寡聚化所需的关键元素，vMIA可以防止这些重要的凋亡步骤。

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    Junhe Ma; Frank Edlich; Guillermo A. Bermejo; Kristi L. Norris; Richard J. Youle; Nico Tjandra;

  • 作者单位

    Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;

    Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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