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首页> 外文期刊>Biochemistry >Formation and Structure of Wild Type Huntingtin Exon-1 Fibrils
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Formation and Structure of Wild Type Huntingtin Exon-1 Fibrils

机译：野生型亨廷顿外来1原纤维的形成和结构

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摘要

The fact that the heritable neurodegenerative disorder Huntington's disease (HD) is autosomal dominant means that there is one wild type and one mutant allele in most HD patients. The CAG repeat expansion in the exon 1 of the protein huntingtin (HTT(ex)1) that causes the disease leads to the formation of HTT fibrils in vitro and vivo. An important question for understanding the molecular mechanism of HD is which role wild type HTT plays for the formation, propagation, and structure of these HTT fibrils. Here we report that fibrils of mutant HTTex1 are able to seed the aggregation of wild type HTTex1, into amyloid fibrils, which in turn can seed the fibril formation of mutant HTTex1. Solid-state NMR and electron paramagnetic resonance data showed that wild type HTTex1, fibrils closely resemble the structure of mutant fibrils, with small differences indicating a less extended fibril core. These data suggest that wild type fibrils can faithfully perpetuate the structure of mutant fibrils in HD. However, wild type HTTex1 monomers have a much higher equilibrium solubility compared to mutant HTTex1, and only a small fraction incorporates into fibrils.
机译：亨廷顿疾病（HD）的遗传性神经退行性疾病（HD）是常染色体显性意味着在大多数高清患者中存在一种野生型和一种突变等位基因。在蛋白质亨廷顿的外显子1中的CAG重复膨胀（HTT（ex）1），导致疾病导致在体外和体内形成HTT原纤维。理解HD的分子机制的重要问题是哪种角色野生型HTT用于这些HTT原纤维的形成，传播和结构。在这里，我们认为突变体Httex1的原纤维能够将野生型HTTEX1的聚集种子成淀粉样蛋白原纤维，这又可以种子突变体HTTEX1的原纤维形成。固态NMR和电子顺磁共振数据显示，野生型HTTEX1，原纤维与突变纤维的结构非常类似于突变纤维的结构，具有较小的延伸的原纤维芯的差异。这些数据表明，野生型原纤维可以忠实地延长高清中突变原纤维的结构。然而，与突变体HTTEX1相比，野生型HTTEX1单体具有更高的平衡溶解度，并且仅少数部分掺入原纤维中。

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  • 来源
    《Biochemistry》 |2017年第28期|共8页
  • 作者

    Isas J. Mario; Langen Andreas; Isas Myles C.; Pandey Nitin K.; Siemer Ansgar B.;

  • 作者单位

    Univ Southern Calif Keck Sch Med Zilkha Neurogenet Inst Dept Biochem &

    Mol Med Los Angeles CA 90033 USA;

    Univ Southern Calif Keck Sch Med Zilkha Neurogenet Inst Dept Biochem &

    Mol Med Los Angeles CA 90033 USA;

    Univ Southern Calif Keck Sch Med Zilkha Neurogenet Inst Dept Biochem &

    Mol Med Los Angeles CA 90033 USA;

    Univ Southern Calif Keck Sch Med Zilkha Neurogenet Inst Dept Biochem &

    Mol Med Los Angeles CA 90033 USA;

    Univ Southern Calif Keck Sch Med Zilkha Neurogenet Inst Dept Biochem &

    Mol Med Los Angeles CA 90033 USA;

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