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中文摘要
翻译
许多使人类衰弱的疾病都与细胞外的错误折叠和聚集有关 球状蛋白质形成富含β-折叠的纤维状沉积物。有相当多的证据 该过程是由本地结构的局部展开启动的,以形成易于聚集的 淀粉样蛋白生成中间体。然后通过成核生长或下坡进行聚集 聚合机制。尽管它们在淀粉样蛋白生成中发挥关键作用,但影响动力学 聚集和重折叠途径之间的划分,人们对其结构知之甚少 淀粉样蛋白中间体,因为它们具有很强的聚集倾向。的目标 目前的建议是应用最先进的核磁共振方法来阐明基本的分子 涉及运甲状腺素蛋白淀粉样变性的事件。运甲状腺素蛋白淀粉样变性与许多 神经退行性疾病和心肌病。甲状腺素运载蛋白的错误折叠和聚集 导致周围神经和心脏的纤维沉积。野生型蛋白的沉积是年龄 相关,而与破坏稳定的基因突变相关的家族性疾病 四级和/或三级结构是早期出现的。拟议的研究将提供新颖的 深入了解野生型转甲状腺素蛋白聚集的基本分子机制 家族突变使天然转甲状腺素蛋白四聚体不稳定并驱动 聚合级联。实时 19F NMR 将用于绘制动力学聚集图 野生型和致病性变体运甲状腺素蛋白,对群体进行表征和定量 在聚集途径上积累的中间体,并检查抑制机制 由小分子和肽组成。多维核磁共振实验将用于阐明 促进四聚体解离的替代构象状态的结构和动力学, 以及在聚集途径上形成的细胞毒性单体和寡聚中间体, 促进聚集和原纤维生长。这项研究将加深我们对 引发四聚体解离并促进进入和的潜在分子事件 沿着聚集级联向下发展,导致野生型人类形成淀粉样蛋白 运甲状腺素蛋白和致病性变异。
英文摘要
Many debilitating human diseases are associated with the extracellular misfolding and aggregation of globular proteins to form fibrillar deposits that are rich in β-sheet. There is considerable evidence that the process is initiated by local unfolding of the native structure to form aggregation-prone amyloidogenic intermediates. Aggregation then proceeds via nucleation-growth or downhill polymerization mechanisms. Despite their key role in amyloidogenesis, influencing the kinetic partitioning between aggregation and refolding pathways, very little is known about the structure of amyloidogenic intermediates because of their strong propensity to aggregate. The goals of the present proposal are to apply state-of-the-art NMR methods to elucidate the fundamental molecular events involved in transthyretin amyloidosis. Transthyretin amyloidosis is associated with numerous neurodegenerative diseases and cardiomyopathies. Misfolding and aggregation of transthyretin leads to fibrous deposits in the peripheral nerves and heart. Deposition of wild type protein is age related, whereas the familial diseases associated with genetic mutations that destabilize the quaternary and/or tertiary structure are early onset. The proposed research will provide novel insights into the fundamental molecular mechanisms by which wild type transthyretin aggregates and by which familial mutations destabilize the native transthyretin tetramer and drive the aggregation cascade. Real-time 19F NMR will be used to map the kinetic aggregation landscape of wild type and pathogenic variant transthyretin, characterize and quantify the population of intermediates that accumulate on the aggregation pathway, and examine mechanisms of inhibition by small molecules and peptides. Multidimensional NMR experiments will be utilized to elucidate the structure and dynamics of an alternate conformational state that promotes tetramer dissociation, and of cytotoxic monomeric and oligomeric intermediates, formed on the aggregation pathway, that promote aggregation and fibril growth. This research will advance our understanding of the underlying molecular events that initiate tetramer dissociation and promote entry into and progression down the aggregation cascade that leads to amyloid formation by both wild type human transthyretin and pathogenic variants.
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Structural characterization of large eukaryotic proteins containing both folded and disordered domains
  • 批准号:
    10552345
  • 项目类别:
  • 资助金额:
    $45.25万
  • 财政年份:
    2023
  • 负责人:
    PETER Edwin WRIGHT
  • 依托单位:
Molecular mechanisms of transthyretin amyloidosis
  • 批准号:
    10115719
  • 项目类别:
  • 资助金额:
    $45.64万
  • 财政年份:
    2020
  • 负责人:
    PETER Edwin WRIGHT
  • 依托单位:
Molecular mechanisms of transthyretin amyloidosis
  • 批准号:
    10599188
  • 项目类别:
  • 资助金额:
    $46.54万
  • 财政年份:
    2020
  • 负责人:
    PETER Edwin WRIGHT
  • 依托单位:
Molecular Basis for Regulation of Cellular Stress Response Pathways by CBP/p300
  • 批准号:
    10436187
  • 项目类别:
  • 资助金额:
    $47.26万
  • 财政年份:
    2018
  • 负责人:
    PETER Edwin WRIGHT
  • 依托单位:
海外基金