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IMPACTING MITOCHONDRIAL FUNCTION THROUGH ALTERED PROTEASE ACTIVITY

通过改变蛋白酶活性影响线粒体功能

基本信息

批准号：
10831938
负责人：
Gabriel C Lander
金额：
$ 10.65万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10831938
关键词：
Address Alzheimer&apos s Disease Apoptotic Award Binding Biological Biological Process Biology Catalytic Domain Cells Cellular biology Chronic Cryoelectron Microscopy Disease Endowment Energy Metabolism Environmental Risk Factor Etiology Genetic Induction Genomic approach Genomics Goals Guanosine Triphosphate Phosphohydrolases Hand Health Hereditary Spastic Paraplegia Inner mitochondrial membrane Membrane Metalloproteases Mitochondria Molecular Morphology Mutation Neurodegenerative Disorders Nucleotides OPA1 gene Parkinson Disease Pathogenesis Pathologic Peptide Hydrolases Proteolysis Regulation Resolution Signal Transduction Site Spinocerebellar Ataxias Stress Structure Structure-Activity Relationship Therapeutic Zinc functional genomics functional/structural genomics human disease insight mitochondrial dysfunction mutation screening pharmacologic proteostasis response therapeutic target

项目摘要

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.

概括线粒体功能障碍是几乎所有疾病的发病和发病机制的病理标志。神经退行性疾病。决定线粒体功能的主要决定因素之一是活性内膜 (IM) 蛋白酶，包括 ATP 依赖性 AAA+ 锌金属蛋白酶 YME1L 和 AFG3L2 和不依赖于 ATP 的锌金属蛋白酶 OMA1。这些蛋白酶调节许多不同的线粒体生物学的各个方面以及保护线粒体免受病理损伤的功能。然而，由遗传或环境因素引起的 IM 蛋白酶活性失衡与病因多样的疾病的发病机制，包括许多神经退行性疾病。尽管如此， IM 蛋白酶调节线粒体生物学的分子机制仍知之甚少。这里，我们正在应用结构驱动的方法来确定 IM 蛋白酶的分子机制在健康和疾病的背景下调节线粒体。我们之前解决了第一个高分辨率 IM AAA+ 蛋白酶 YME1 和 AFG3L2 的结构。我们的结构表明这两种蛋白酶采用保守的核苷酸驱动的交接机制将底物易位到特权位置用于蛋白水解的蛋白水解室。令人惊讶的是，我们还发现了 YME1 的独特结构特征和 AFG3L2 整合到这种保守的易位机制中，显着影响蛋白酶活性稳定。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学功能对于线粒体的调节很重要。致地址为此，我们结合使用冷冻电子显微镜和细胞生物学来确定结构如何 IM AAA+ 蛋白酶的差异影响其机械化学循环并使蛋白酶能够发挥作用独特的生物学功能。这将揭示 IM AAA+ 的分子机制的新见解蛋白酶在健康和疾病中调节线粒体。此外，我们正在利用这两种方法来扩展这项研究功能基因组和结构方法建立结构-功能关系，解释不依赖 ATP 的应激激活 IM 蛋白酶 OMA1（一种蛋白酶）的激活和蛋白水解活性其失调与许多人类相关的病理性线粒体功能障碍有关疾病。通过这些努力，我们将定义 IM 蛋白酶如何利用不同的结构特征来执行适当调节线粒体蛋白质稳态和功能所需的无数生物功能。此外，我们将揭示改变的病理学和潜在治疗意义的新见解。线粒体 IM 蛋白酶在人类疾病中的活性并确定药理靶向的新机会 IM 蛋白酶可减轻与许多神经退行性疾病相关的线粒体功能障碍。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DELE1 oligomerization promotes integrated stress response activation.

DELE1 寡聚化促进整合应激反应激活。

DOI：
10.1038/s41594-023-01061-0
发表时间：
2023
期刊：
Nature structural & molecular biology
影响因子：
16.8
作者：
Yang,Jie;Baron,KelseyR;Pride,DanielE;Schneemann,Anette;Guo,Xiaoyan;Chen,Wenqian;Song,AlbertS;Aviles,Giovanni;Kampmann,Martin;Wiseman,RLuke;Lander,GabrielC
通讯作者：
Lander,GabrielC

Structures of the human LONP1 protease reveal regulatory steps involved in protease activation.

DOI：
10.1038/s41467-021-23495-0
发表时间：
2021-05-28
期刊：
Nature communications
影响因子：
16.6
作者：
Shin M;Watson ER;Song AS;Mindrebo JT;Novick SJ;Griffin PR;Wiseman RL;Lander GC
通讯作者：
Lander GC

Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming.

DOI：
10.1038/s41589-020-0584-z
发表时间：
2020-10
期刊：
Nature chemical biology
影响因子：
14.8
作者：
Grandjean JMD;Madhavan A;Cech L;Seguinot BO;Paxman RJ;Smith E;Scampavia L;Powers ET;Cooley CB;Plate L;Spicer TP;Kelly JW;Wiseman RL
通讯作者：
Wiseman RL

Cryo-EM structure of hexameric yeast Lon protease (PIM1) highlights the importance of conserved structural elements.