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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the GTPase Rac2
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Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the GTPase Rac2

机译：磷脂酶D2（PLD2）是GTPase Rac2的鸟嘌呤核苷酸交换因子（GEF）

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摘要

We have discovered that the enzyme phospholipase D2 (PLD2) binds directly to the small GTPase Rac2, resulting in PLD2 functioning as a guanine nucleotide exchange factor (GEF), because it switches Rac2 from the GDP-bound to the GTP-bound states. This effect is large enough to be meaningful (～72% decrease for GDP dissociation and 300% increase for GTP association, both with PLD2), it has a half-time of ～7 min, is enhanced with increasing PLD2 concentrations, and compares favorably with other known GEFs, such as Vav-1. The PLD2-Rac2 protein-protein interaction is sufficient for the GEF function, because it can be demonstrated in vitro with just recombinant proteins without lipid substrates, and a catalytically inactive lipase (PLD2-K758R) has GEF activity. Apart from this function, exogenous phosphatidic acid by itself (300 pM) increases GTP binding and enhances PLD2-K758R-mediated GTP binding (by ～34%) but not GDP dissociation. Regarding the PLD2-Rac2 protein-protein association, it involves, for PLD2, residues 263-266 within a Cdc42/Rac interactive binding region in the PH domain, as well as the PX domain, and it involves, for Rac2, residue N17 within its Switch-1 region. PLD2's GEF function is demonstrated in living cells, because silencing PLD2 results in reduced Rac2 activity, whereas PLD2-initiated Rac2 activation enhances cell adhesion, chemotaxis, and phagocytosis. There are several known GEFs, but we report that this GEF is harbored in a phospholipase. The benefit to the cell is that PLD2 brings spatially separated molecules together in a membrane environment, ready for fast intracellular signaling and cell function.
机译：我们发现，磷脂酶D2（PLD2）酶直接与小GTPase Rac2结合，导致PLD2发挥鸟嘌呤核苷酸交换因子（GEF）的作用，因为它将Rac2从与GDP结合的状态转换为与GTP结合的状态。该效应足够大以至于有意义（与PLD2一起，GDP离解的降低约72％，与GTP关联的增加300％），它的半衰期为〜7分钟，随着PLD2浓度的增加而增强，并且比较有利与其他已知的GEF，例如Vav-1。 PLD2-Rac2蛋白质-蛋白质相互作用足以实现GEF功能，因为可以在体外仅使用重组蛋白而不使用脂质底物进行证明，而无催化活性的脂肪酶（PLD2-K758R）具有GEF活性。除此功能外，外源磷脂酸本身（300 pM）会增加GTP结合并增强PLD2-K758R介导的GTP结合（〜34％），但不会解离GDP。关于PLD2-Rac2蛋白-蛋白质的结合，对于PLD2而言，它涉及PH结构域以及PX结构域中的Cdc42 / Rac相互作用结合区内的残基263-266，对于Rac2而言，它涉及其中的残基N17。其Switch-1区域。 PLD2的GEF功能在活细胞中得到了证明，因为沉默PLD2会导致Rac2活性降低，而PLD2引发的Rac2激活则会增强细胞粘附，趋化性和吞噬作用。有几种已知的GEF，但我们报告此GEF包含在磷脂酶中。对细胞的好处是PLD2在膜环境中将空间分离的分子聚集在一起，为快速的细胞内信号传递和细胞功能做好了准备。

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    Madhu Mahankali; Hong-Juan Peng; Karen M. Henkels; Mary C. Dinauer; Julian Gomez-Cambronero;

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    Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435;

    Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435;

    Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435;

    Department of Pediatrics (Division of Hematology/Oncology) and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435;

  • 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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