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中文摘要
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摘要 线粒体功能障碍是几乎所有神经退行性疾病发病和发病的病理标志 疾病。决定线粒体功能的主要决定因素之一是内膜的活性 (IM)包括依赖于ATP的AAA锌金属蛋白酶YME1L和AFG3L2以及ATP- 独立锌金属蛋白酶OMA1。这些蛋白水解酶调节线粒体的许多不同方面 保护线粒体免受病理性侮辱的生物学和功能。然而,IM活动中的不平衡 由遗传或环境因素诱导的蛋白水解酶与多种病因相关。 包括许多神经退行性疾病在内的疾病。尽管如此,IM的分子机制 蛋白水解酶调节线粒体生物学仍然知之甚少。在这里,我们应用了一种结构驱动的 在此背景下确定IM蛋白酶调节线粒体的分子机制的方法 健康和疾病。我们之前解决了IM AAA蛋白水解酶YME1的第一个高分辨结构 和AFG3L2。我们的结构表明,这两种蛋白酶都使用保守的核苷酸驱动的、手性的. 将底物转移到特制的蛋白质水解室以进行蛋白质分解的过手机制。令人惊讶的是, 我们还鉴定了整合到这种保守易位中的YME1和AFG3L2的独特结构特征 显著影响酶活力和稳定性的机理。在这里,我们假设这些独特的 结构差异赋予IM蛋白酶不同的机制和生物功能 因为它们对线粒体的调节。为了解决这个问题,我们使用了低温电子显微镜的组合 和细胞生物学来确定IM AAA酶的结构差异如何影响它们的机械力化学 循环,使蛋白水解酶执行不同的生物功能。这将揭示对分子的新见解 IM AAA蛋白酶在健康和疾病中调节线粒体的机制。此外,我们正在 利用功能基因组和结构方法扩展这项研究,以建立结构-功能 解释ATP非依赖性、应激激活的IM的激活和蛋白分解活性的关系 蛋白水解酶OMA1--一种与病理性线粒体功能障碍有关的酶 与许多人类疾病有关。通过这些努力,我们将定义IM蛋白水解酶如何利用不同的 执行适当调节线粒体所需的多种生物学功能的结构特征 蛋白质平衡和功能。此外,我们将揭示病理和潜在的治疗方面的新见解 线粒体IM蛋白酶活性改变在人类疾病中的意义并确定新的机会 药物靶向IM蛋白酶可缓解与多发性硬化相关的线粒体功能障碍 神经退行性疾病。
英文摘要
SUMMARY Mitochondrial dysfunction is a pathologic hallmark in the onset and pathogenesis of nearly all neurodegenerative diseases. One of the primary determinants in dictating mitochondrial function is the activity of inner membrane (IM) proteases including the ATP-dependent AAA+ zinc metalloproteases YME1L and AFG3L2 and the ATP- independent zinc metalloprotease OMA1. These proteases regulate many different aspects of mitochondrial biology and function to protect mitochondria from pathologic insults. However, imbalances in the activity of IM proteases induced by genetic or environmental factors are implicated in the pathogenesis of etiologically-diverse diseases including many neurodegenerative disorders. Despite this, the molecular mechanisms by which IM proteases regulate mitochondrial biology remain poorly understood. Here, we are applying a structure-driven approach to determine the molecular mechanisms by which IM proteases regulate mitochondria in the context of health and disease. We previously solved the first high-resolution structures of the IM AAA+ proteases YME1 and AFG3L2. Our structures showed that these two proteases employ a conserved nucleotide-driven, hand- over-hand mechanism to translocate substrates into a privileged proteolytic chamber for proteolysis. Surprisingly, we also identified unique structural features of YME1 and AFG3L2 that integrate into this conserved translocation mechanism to distinctly influence protease activity and stability. Here, we hypothesize that these unique structural differences endow IM proteases with different mechanistic and biologic functions important for their regulation of mitochondria. To address this, we are using a combination of cryo-electron microscopy and cell biology to determine how structural differences in IM AAA+ proteases influence their mechanochemical cycle and enable proteases to perform distinct biological functions. This will reveal new insights into the molecular mechanisms by which IM AAA+ proteases regulate mitochondria in health and disease. Furthermore, we are extending this study utilizing both functional genomic and structural approaches to establish a structure-function relationship that explains the activation and proteolytic activity of the ATP-independent, stress-activated IM protease OMA1 – a protease whose dysregulation is implicated in the pathologic mitochondrial dysfunction associated with many human diseases. Through these efforts, we will define how IM proteases utilize distinct structural features to perform the myriad of biological functions required for the proper regulation of mitochondrial proteostasis and function. Furthermore, we will reveal new insights into the pathologic and potentially therapeutic implications of altered mitochondrial IM protease activity in human disease and identify new opportunities to pharmacologically target IM proteases to mitigate mitochondrial dysfunction associated with many neurodegenerative disorders.
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Developing minimal purification cryo-EM to understand mitochondrial myopathies
  • 批准号:
    10732697
  • 项目类别:
  • 资助金额:
    $44.41万
  • 财政年份:
    2023
  • 负责人:
    Gabriel C Lander
  • 依托单位:
High-speed direct detector for cryo electron microscopy
  • 批准号:
    10440962
  • 项目类别:
  • 资助金额:
    $60.0万
  • 财政年份:
    2022
  • 负责人:
    Gabriel C Lander
  • 依托单位:
Development of a pipeline for parallel elucidation of protein structures
  • 批准号:
    10434001
  • 项目类别:
  • 资助金额:
    $26.63万
  • 财政年份:
    2021
  • 负责人:
    Gabriel C Lander
  • 依托单位:
Development of a pipeline for parallel elucidation of protein structures
  • 批准号:
    10231713
  • 项目类别:
  • 资助金额:
    $22.19万
  • 财政年份:
    2021
  • 负责人:
    Gabriel C Lander
  • 依托单位: