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首页> 外文期刊>Journal of Molecular Biology >Effect of serine phosphorylation and ser25 phospho-mimicking mutations on nuclear localisation and ligand interactions of annexin A2
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Effect of serine phosphorylation and ser25 phospho-mimicking mutations on nuclear localisation and ligand interactions of annexin A2

机译：丝氨酸磷酸化和SER25磷酸磷模拟突变对膜蛋白A2核定位和配体相互作用的影响

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摘要

Annexin A2 (AnxA2) interacts with numerous ligands, including calcium, lipids, mRNAs and intracellular and extracellular proteins. Different post-translational modifications participate in the discrimination of the functions of AnxA2 by modulating its ligand interactions. Here, phospho-mimicking mutants (AnxA2-S25E and AnxA2-S25D) were employed to investigate the effects of Ser25 phosphorylation on the structure and function of AnxA2 by using AnxA2-S25A as a control. The overall α-helical structure of AnxA2 is not affected by the mutations, since the thermal stabilities and aggregation tendencies of the mutants differ only slightly from the wild-type (wt) protein. Unlike wt AnxA2, all mutants bind the anxA2 3′ untranslated region and β-γ-G-Actin with high affinity in a Ca 2 +-independent manner. AnxA2-S25E is not targeted to the nucleus in transfected PC12 cells. In vitro phosphorylation of AnxA2 by protein kinase C increases its affinity to mRNA and inhibits its nuclear localisation, in accordance with the data obtained with the phospho-mimicking mutants. Ca 2 +-dependent binding of wt AnxA2 to phosphatidylinositol, phosphatidylinositol-3-phosphate, phosphatidylinositol-4-phosphate and phosphatidylinositol-5-phosphate, as well as weaker but still Ca 2 +-dependent binding to phosphatidylserine and phosphatidylinositol- 3,5-bisphosphate, was demonstrated by a protein-lipid overlay assay, whereas binding of AnxA2 to these lipids, as well as its binding to liposomes, is inhibited by the Ser25 mutations. Thus, introduction of a modification (mutation or phosphorylation) at Ser25 appears to induce a conformational change leading to increased accessibility of the mRNA- and G-Actin-binding sites in domain IV independent of Ca2 + levels, while the Ca2 +-dependent binding of AnxA2 to phospholipids is attenuated.
机译：Annexin A2（ANXA2）与许多配体相互作用，包括钙，脂质，mRNA和细胞内和细胞外蛋白。不同的翻译后修改通过调节其配体相互作用来参与ANXA2的功能。这里，使用磷酸模拟突变体（ANXA2-S25E和ANXA2-S25D）来研究SER25磷酸化对ANXA2作为对照的影响的影响。 ANXA2的总体α-螺旋结构不受突变的影响，因为突变体的热稳定性和聚集趋势仅略微不同于野生型（WT）蛋白。与WT ANXA2不同，所有突变体都以高亲和力粘合ANXA2 3'未转化的区域和β-γ-G-肌动蛋白，以Ca 2 +依赖性方式具有高亲和力。 ANXA2-S25E未靶向转染PC12细胞中的核。通过蛋白质激酶C通过蛋白激酶C的体外磷酸化增加其对mRNA的亲和力并根据用磷酸模拟突变体获得的数据来抑制其核定位。加入WT ANXA2至磷脂酰肌醇，磷脂酰肌醇-3-磷酸酯，磷脂酰肌醇-4-磷酸盐和磷脂酰肌醇-5-磷酸三磷酸酯，较弱但仍然Ca 2 +依赖性与磷脂酰丝氨酸和磷脂酰肌醇-3,5蛋白质 - 脂质覆盖测定证明了 - 磷酸，而Ser25突变抑制了ANXA2与这些脂质的结合，以及与脂质体的结合。因此，Ser25的改性（突变或磷酸化）的引入似乎诱导构象变化，导致域IV中mRNA和G-肌动蛋白结合位点的可及性增加，而CA2 +依赖性结合ANXAPIPIPS的抑制。

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  • 来源
    《Journal of Molecular Biology》 |2014年第13期|共14页
  • 作者

    GrindheimA.K.; Holl?sH.; RamirezJ.; SarasteJ.; TravéG.; VedelerA.;

  • 作者单位

    Department of Biomedicine University of Bergen N-5009 Bergen Norway Molecular Imaging Center;

    Department of Biomedicine University of Bergen N-5009 Bergen Norway;

    Biotechnologie et Signalisation Cellulaire UMR 7242 Ecole Supérieure de Biotechnologie de;

    Department of Biomedicine University of Bergen N-5009 Bergen Norway Molecular Imaging Center;

    Biotechnologie et Signalisation Cellulaire UMR 7242 Ecole Supérieure de Biotechnologie de;

    Department of Biomedicine University of Bergen N-5009 Bergen Norway;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子生物学;
  • 关键词

    3′ untranslated region; G-Actin; mRNA; phospholipid; secondary structure;

    机译：3'未转换区域;G-肌动蛋白;mRNA;磷脂;二级结构;

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