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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Out-of-register β-sheets suggest a pathway to toxic amyloid aggregates
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Out-of-register β-sheets suggest a pathway to toxic amyloid aggregates

机译:失衡的β-折叠提示有毒的淀粉样蛋白聚集体的途径

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摘要

Although aberrant protein aggregation has been conclusively linked to dozens of devastating amyloid diseases, scientists remain puzzled about the molecular features that render amyloid fibrils or small oligomers toxic. Here, we report a previously unobserved type of amyloid fibril that tests as cytotoxic: one in which the strands of the contributing β-sheets are out of register. In all amyloid fibrils previously characterized at the molecular level, only in-register β-sheets have'been observed, in which each strand makes its full complement of hydrogen bonds with the strands above and below it in the fibril. In out-of-register sheets, strands are sheared relative to one another, leaving dangling hydrogen bonds. Based on this finding, we designed out-of-register β-sheet amyloid mimics, which form both cylindrin-like oligomers and fibrils, and these mimics are cytotoxic. Structucal and energetic considerations suggest that out-of-register fibrils can readily convert to toxic cylindrins. We propose that out-of-register β-sheets and their related cylindrins are part of a toxic amyloid pathway, which is distinct from the more energetically favored in-register amyloid pathway.
机译:尽管异常的蛋白质聚集已被确定地与数十种破坏性的淀粉样蛋白疾病联系在一起,但科学家仍对使淀粉样蛋白原纤维或小的低聚物具有毒性的分子特征感到困惑。在这里,我们报告了一种先前未被观察到的淀粉样蛋白原纤维,它被测试为具有细胞毒性:在该淀粉样原纤维中,贡献性β-折叠的链不重合。在先前在分子水平上表征过的所有淀粉样原纤维中,仅观察到配准β-折叠,其中每条链与原纤维上方和下方的链完全形成氢键互补。在套准不齐的薄片中,股线彼此剪切,留下悬挂的氢键。基于此发现,我们设计了失配的β-sheet淀粉样蛋白模拟物,它们既形成柱状蛋白样低聚物又形成原纤维,并且这些模拟物具有细胞毒性。结构和能量方面的考虑表明,配准失调的原纤维可以轻易转化为有毒的圆柱蛋白。我们提出,配准外的β-折叠及其相关的圆柱蛋白是毒性淀粉样蛋白途径的一部分,这与能量更受支持的配准淀粉样蛋白途径不同。

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  • 作者单位

    UCLA-DOE Institute for Genomics and Proteomics, The Howard Hughes Medical Institute, Molecular Biology Institute, Molecular Genetics, University of California, Los Angeles, CA 90095;

    UCLA-DOE Institute for Genomics and Proteomics, The Howard Hughes Medical Institute, Molecular Biology Institute, Molecular Genetics, University of California, Los Angeles, CA 90095,Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;

    UCLA-DOE Institute for Genomics and Proteomics, The Howard Hughes Medical Institute, Molecular Biology Institute, Molecular Genetics, University of California, Los Angeles, CA 90095;

    Departments of Chemistry and, University of California, Irvine, CA 92697-2025;

    UCLA-DOE Institute for Genomics and Proteomics, The Howard Hughes Medical Institute, Molecular Biology Institute, Molecular Genetics, University of California, Los Angeles, CA 90095;

    UCLA-DOE Institute for Genomics and Proteomics, The Howard Hughes Medical Institute, Molecular Biology Institute, Molecular Genetics, University of California, Los Angeles, CA 90095;

    Departments of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-2025;

    Molecular Biology Institute and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;

    Molecular Biology Institute and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;

    Departments of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-2025;

    Departments of Chemistry and, University of California, Irvine, CA 92697-2025;

    UCLA-DOE Institute for Genomics and Proteomics, The Howard Hughes Medical Institute, Molecular Biology Institute, Molecular Genetics, University of California, Los Angeles, CA 90095;

  • 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

    x-ray crystallography; BAMs;

    机译:X射线晶体学BAM;

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