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首页> 外文期刊>Biochemistry >Requirements for Skp1 Processing by Cytosolic Prolyl 4(trans)-Hydroxylase and alpha-N-Acetylglucosaminyltransferase Enzymes Involved in O-2 Signaling in Dictyostelium
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Requirements for Skp1 Processing by Cytosolic Prolyl 4(trans)-Hydroxylase and alpha-N-Acetylglucosaminyltransferase Enzymes Involved in O-2 Signaling in Dictyostelium

机译：Cytosolic脯氨酸4（反式） - 羟基酶和α-N-乙酰葡糖胺氨基氨基转移酶的SKP1处理要求参与O-2信号传导在Dictyostelium中的酶

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摘要

The social amoeba Dictyostelium expresses a hypoxia inducible factor-alpha (HIF alpha) type prolyl 4-hydroxylase (P4H1) and an alpha-N-acetylglucosaminyltransferase (Gnt1) that sequentially modify proline-143 of Skp1, a subunit of the SCF (Skp1/Cullin/F-box protein) class of E3 ubiquitin ligases. Prior genetic studies have implicated Skp1 and its modification by these enzymes in O_2 regulation of development, suggesting the existence of an ancient O_2-sensing mechanism related to modification of the transcription factor HIF alpha by animal prolyl 4-hydroxylases (PHDs). To better understand the role of Skp1 in P4H1-dependent O_2 signaling, biochemical and biophysical studies were conducted to characterize the reaction product and the basis of Skp1 substrate selection by P4H1 and Gnt1. ~1H NMR demonstrated formation of 4(trans)-hydroxyproline as previously found for HIF alpha, and highly purified P4H1 was inhibited by Krebs cycle intermediates and other compounds that affect animal P4Hs. However, in contrast to hydroxylation of HIF alpha by PHDs, P4H1 depended on features of full-length Skp1, based on truncation, mutagenesis, and competitive inhibition studies. These features are conserved during animal evolution, as even mammalian Skp1, which lacks the target proline, became a good substrate upon its restoration. P4H1 recognition may depend on features conserved for SCF complex formation as heterodimerization with an F-box protein blocked Skp1 hydroxylation. The hydroxyproline-capping enzyme Gnt1 exhibited similar requirements for Skp1 as a substrate. These and other findings support a model in which the protist P4H1 conditionally hydroxylates Skp1 of E3~(SCF) ubiquitin ligases to control half-lives of multiple targets, rather than the mechanism of animal PHDs where individual proteins are hydroxylated leading to ubiquitination by the evolutionarily related E3~(VBC) ubiquitin ligases.
机译：社交amoeba dictyostelium表达缺氧诱导因子-α（HIFα）α（HIF alpha）型脯氨酰4-羟基化酶（P4H1）和α-n-乙酰葡糖胺氨基丙烯酰转移酶（GNT1），其顺序地修饰SKP1的SKP1的脯氨酸-143，SCF的亚基（SKP1 / Cullin / F-Box蛋白）E3泛素连接酶的类别。先前的遗传研究具有牵连的SKP1及其在O_2发育中的调节中的这些酶的修饰，表明动物脯氨酰4-羟基酶（PHDS）的转录因子HIFα的改变有关的古代O_2感测机制。为了更好地了解SKP1在P4H1依赖性的O_2信号传导中的作用，进行生化和生物物理研究以表征反应产物和P4H1和GNT1的SKP1基板选择的基础。 〜1H NMR证明了以前发现的4（反式） - 羟基脯氨酸，如先前发现的HIFα，并且通过克雷斯循环中间体和影响动物P4HS的其他化合物抑制高度纯化的P4H1。然而，与HIFα的羟基化对比通过PHDS，P4H1依赖于全长SKP1的特征，基于截断，诱变和竞争性抑制研究。这些特征在动物进化过程中被保守，甚至缺乏靶脯氨酸的哺乳动物SKP1在恢复后成为良好的基质。 P4H1识别可取决于SCF复合物形成的特征，作为与F型盒子蛋白阻断的SKP1羟基化的异二聚体。羟脯氨酸 - 封端酶GNT1表现出与底物的SKP1类似的要求。这些和其他发现支持一种模型，其中E3〜（SCF）泛素连接酶的原体P4H1条件羟基化物SKP1以控制多个靶标的半衰期，而不是动物疫苗的机制，其中单个蛋白质是羟基化的，导致泛素化的泛素化相关E3〜（VBC）泛素连接酶。

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  • 来源
    《Biochemistry》 |2011年第10期|共14页
  • 作者

    van der Wel H; Johnson JM; Xu YC; Karunaratne CV; Wilson KD; Vohra Y; Boons GJ; Taylor CM; Bendiak B; West CM;

  • 作者单位

    Department of Biochemistry and Molecular Biology Oklahoma Center for Medical Glycobiology University of Oklahoma Health Sciences Center Oklahoma City Oklahoma 73104 United States;

    Department of Biochemistry and Molecular Biology Oklahoma Center for Medical Glycobiology University of Oklahoma Health Sciences Center Oklahoma City Oklahoma 73104 United States;

    Department of Biochemistry and Molecular Biology Oklahoma Center for Medical Glycobiology University of Oklahoma Health Sciences Center Oklahoma City Oklahoma 73104 United States;

    Department of Chemistry 742 Choppin Hall Louisiana State University Baton Rouge Louisiana 70803 United States;

    Department of Biochemistry and Molecular Biology Oklahoma Center for Medical Glycobiology University of Oklahoma Health Sciences Center Oklahoma City Oklahoma 73104 United States;

    Department of Chemistry and Complex Carbohydrate Research Center 315 Riverbend Road University of Georgia Athens Georgia 30602 United States;

    Department of Chemistry and Complex Carbohydrate Research Center 315 Riverbend Road University of Georgia Athens Georgia 30602 United States;

    Department of Chemistry 742 Choppin Hall Louisiana State University Baton Rouge Louisiana 70803 United States;

    Department of Cell and Developmental Biology and Structural Biology and Biophysics Program University of Colorado Denver Anschutz Medical Campus Mail Stop 8108 RC-1 South Building L18-12120 12801 East 17th Avenue Aurora Colorado 80045 United States;

    Department of Biochemistry and Molecular Biology Oklahoma Center for Medical Glycobiology University of Oklahoma Health Sciences Center Oklahoma City Oklahoma 73104 United States;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    Requirements; Cytosolic; Enzymes;

    机译：要求;细胞溶质;酶;

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