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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Interaction of phosphodiesterase 3A with brefeldin A-inhibited guanine nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1 activity
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Interaction of phosphodiesterase 3A with brefeldin A-inhibited guanine nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1 activity

机译：磷酸二酯酶3A与布雷菲德菌素A抑制鸟嘌呤核苷酸交换蛋白BIG1和BIG2的相互作用和对ARF1活性的影响

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摘要

ADP-ribosylation factors (ARFs) have crucial roles in vesicular trafficking. Brefeldin A-inhibited guanine nucleotide-exchange proteins (BIG)1 and BIG2 catalyze the activation of class I ARFs by accelerating replacement of bound GDP with GTP. Several additional and differing actions of BIG1 and BIG2 have been described. These include the presence in BIG2 of 3 A kinase-anchoring protein (AKAP) domains, one of which is identical in BIG1. Proteins that contain AKAP sequences act as scaffolds for the assembly of PKA with other enzymes, substrates, and regulators in complexes that constitute molecular machines for the reception, transduction, and integration of signals from cAMP or other sources, which are initiated, propagated, and transmitted by chemical, electrical, or. Mechanical means. Specific depletion of HeLa cell PDE3A with small interfering RNA significantly decreased membrane-associated BIG1 and BIG2, which by confocal immunofluorescence microscopy were widely dispersed from an initial perinuclear Golgi concentration. Concurrently, activated ARF1-GTP was significantly decreased. Selective inhibition of PDE3A by 1-h incubation of cells with cilosta-mide similarly decreased membrane-associated BIG1. We suggest that decreasing PDE3A allowed cAMP to accumulate in microdo-mains where its enzymatic activity limited cAMP concentration. There, cAMP-activated PKA phosphorylated BIG1 and BIG2 (AKAPs for assembly of PKA, PDE3A, and other molecules), which decreased their GEP activity and thereby amounts of activated ARF1-GTP. Thus, PDE3A in these BIG1 and BIG2 AKAP complexes may contribute to the regulation of ARF function via limitation of cAMP effects with spatial and temporal specificity.
机译：ADP-核糖基化因子（ARF）在水泡运输中起关键作用。布雷菲德菌素A抑制的鸟嘌呤核苷酸交换蛋白（BIG）1和BIG2通过加速用GTP替代结合的GDP来催化I类ARF的激活。已经描述了BIG1和BIG2的几个其他不同动作。这些包括在BIG2中存在3 A激酶锚定蛋白（AKAP）域，其中一个在BIG1中相同。包含AKAP序列的蛋白质可充当支架，将PKA与其他酶，底物和调节剂组装成复合物，这些复合物构成了分子机器，用于接收，转导和整合来自cAMP或其他来源的信号，这些信号被引发，传播和传播。通过化学，电气或其他方式传输。机械手段。 HeLa细胞PDE3A的特异性耗竭与小的干扰RNA显着降低了与膜相关的BIG1和BIG2，通过共聚焦免疫荧光显微镜观察，它们从初始的核周高尔基体浓度开始被广泛分散。同时，活化的ARF1-GTP显着降低。通过将细胞与西洛司他汀孵育1小时，对PDE3A的选择性抑制同样会降低与膜相关的BIG1。我们建议降低PDE3A可使cAMP在其酶活性限制cAMP浓度的微主干中积累。在那里，cAMP激活的PKA磷酸化了BIG1和BIG2（用于组装PKA，PDE3A和其他分子的AKAP），从而降低了它们的GEP活性，从而降低了活化的ARF1-GTP的量。因此，这些BIG1和BIG2 AKAP复合物中的PDE3A可能通过以空间和时间特异性限制cAMP效应而有助于ARF功能的调节。

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    Ermanno Puxeddu; Marina Uhart; Chun-Chun Li; Faiyaz Ahmad; Gustavo Pacheco-Rodriguez; Vincent C. Manganiello; Joel Moss; Martha Vaughan;

  • 作者单位

    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

    Translational Medicine Branch, 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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