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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Nonnative interactions regulate folding and switching of myristoylated protein
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Nonnative interactions regulate folding and switching of myristoylated protein

机译:非天然相互作用调节肉豆蔻酰化蛋白的折叠和转换

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摘要

We present an integrated experimental and computational study of the molecular mechanisms by which myristoylation affects protein folding and function, which has been little characterized to date. Myristoylation, the covalent linkage of a hydrophobic C14 fatty acyl chain to the N-terminal glycine in a protein, is a common modification that plays a critical role in vital regulated cellular processes by undergoing reversible energetic and conformational switching. Coarse-grained folding simulations for the model pH-dependent actin- and membrane-binding protein hisactophilin reveal that non-native hydrophobic interactions of the myristoyl with the protein as well as nonnative electrostatic interactions have a pronounced effect on folding rates and thermodynamic stability. Folding measurements for hydrophobic residue mutations of hisactophilin and atomistic simulations indicate that the nonnative interactions of the myristoyl group in the folding transition state are nonspecific and robust, and so smooth the energy landscape for folding. In contrast, myristoyl interactions in the native state are highly specific and tuned for sensitive control of switching functionality. Simulations and amide hydrogen exchange measurements provide evidence for increases as well as decreases in stability localized on one side of the myristoyl binding pocket in the protein, implicating strain and altered dynamics in switching. The effects of folding and function arising from myristoylation are profoundly different from the effects of other post-transiational modifications.
机译:我们目前对肉豆蔻酰化影响蛋白质折叠和功能的分子机制进行了综合的实验和计算研究,迄今为止尚无定论。肉豆蔻酰基化是疏水性C14脂肪酰基链与蛋白质N端甘氨酸的共价键,是一种常见的修饰,通过经历可逆的能量和构象转换,在重要的调控细胞过程中起着至关重要的作用。模型依赖pH的肌动蛋白和膜结合蛋白组织亲脂蛋白的粗粒折叠模拟显示,肉豆蔻酰基与蛋白质的非天然疏水相互作用以及非天然静电相互作用对折叠速率和热力学稳定性都有显着影响。亲脂蛋白疏水残基突变的折叠测量和原子模拟表明,在折叠过渡状态下肉豆蔻酰基基团的非天然相互作用是非特异性和鲁棒性的,因此使折叠的能量格局变得平滑。相比之下,天然状态下的肉豆蔻酰基相互作用是高度特异性的,并经过调节可敏感地控制开关功能。模拟和酰胺氢交换测量提供了蛋白质中肉豆蔻酰结合口袋一侧的稳定性增加和降低的证据,这牵涉到应变和转换过程中动力学的改变。肉豆蔻酰基化产生的折叠和功能的影响与其他后翻译修饰的影响有很大不同。

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  • 作者单位

    Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel;

    Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo, Waterloo, ON, Canada N2L 3G1;

    Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo, Waterloo, ON, Canada N2L 3G1;

    Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo, Waterloo, ON, Canada N2L 3G1;

    Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel;

    Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo, Waterloo, ON, Canada N2L 3G1;

    Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo, Waterloo, ON, Canada N2L 3G1;

    Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo, Waterloo, ON, Canada N2L 3G1;

    Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo, Waterloo, ON, Canada N2L 3G1;

    Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel;

  • 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);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    coarse-grained simulation; funnel landscape; β-trefoil;

    机译:粗粒度模拟;漏斗景观;β-三叶草;

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