Structure, Function, and Mechanism of a Mitochondrial Chaperone

线粒体伴侣的结构、功能和机制

基本信息

批准号：
10316887
负责人：
Francis T.F. Tsai
金额：
$ 52.81万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316887
关键词：
ATP phosphohydrolase Acute Myelocytic Leukemia Address Adult Aging Alzheimer&apos s Disease Animals Ankyrin Repeat Antineoplastic Agents Apoptosis Applications Grants Atherosclerosis Binding Binding Proteins Biological Process Cardiovascular Diseases Cells Cessation of life Clinical Colorectal Cancer Complex Crista ampullaris Cryoelectron Microscopy Crystallization Development Disease Drug Targeting Engineering Family Functional disorder Health Human Huntington Disease Hybrids In Vitro Inborn Errors of Metabolism Life Maintenance Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Metabolic Diseases Missense Mutation Mitochondria Mitochondrial Proteins Molecular Molecular Chaperones Molecular Conformation Morphology Mutagenesis Mutation N-terminal Neonatal Nerve Degeneration Neurodegenerative Disorders Neutropenia Non-Insulin-Dependent Diabetes Mellitus Nucleotides Organelles Outcome Parkinson Disease Pathologic Peptide Hydrolases Peptides Physiological Plant Roots Process Protein Engineering Proteins Proteomics Public Health Quality Control Reporting Research Resolution Role Stress Structure Structure-Activity Relationship System Technology Time X-Ray Crystallography acute myeloid leukemia cell biological adaptation to stress cancer cell cell type cerebral atrophy developmental disease disease-causing mutation human disease malignant breast neoplasm member microbial misfolded protein mitochondrial dysfunction mortality neoplastic cell novel novel therapeutic intervention particle prevent protein aggregation protein folding protein misfolding proteostasis surveillance strategy three dimensional structure unfoldase

项目摘要

SUMMARY Mitochondria function as the powerhouses of the cell and are essential to cellular and organismal health. Conversely, mitochondrial degeneration and dysfunction are hallmarks of human diseases including developmental and metabolic disorders, type 2 diabetes, Alzheimer's disease, Parkinson's disease, Huntington's disease, cancer, atherosclerosis, and cardiovascular diseases. Consequently, several surveillance strategies have evolved consisting of molecular chaperones and energy-dependent proteases that protect mitochondria from damage. Mitochondria possess a representative member of every stress-inducible chaperone family; thus, providing a paradigm to elucidate the function of the ensemble of molecular chaperones in proteostasis maintenance. It is widely appreciated that molecular chaperones provide the first line of defense against protein misfolding by promoting the correct folding and preventing aberrant folding and aggregation. Mitochondrial chaperones are also widely expressed in most tumor cell types, including colorectal, breast, prostate, and ovarian cancer, which have the highest mortality rates, indicating a central role of mitochondrial chaperones in the immortalization of cancer cells and underscoring their significance as promising anti-cancer drug targets. The broad and long-term research objective is to provide a molecular understanding how mitochondrial chaperones maintain proteostasis under physiological conditions and how their function is modulated in pathological states. Specifically, we will focus on the structural analysis of a novel ATP-dependent mitochondrial chaperone using X-ray crystallography and cryoEM, determine its protein interactome using functional proteomics, and use a structure-guided mutagenesis approach to elucidate its biological function in vitro and in living cells. Addressing an important biomedical problem using a multi-pronged approach at different resolution and time scale underscores the significance and impact of the proposed research.

概括线粒体作为细胞的动力室，对于细胞和有机体的健康至关重要。相反，线粒体变性和功能障碍是人类疾病的标志，包括发育和代谢障碍、2 型糖尿病、阿尔茨海默病、帕金森病、亨廷顿舞蹈症疾病、癌症、动脉粥样硬化和心血管疾病。因此，多种监控策略已进化出由保护线粒体的分子伴侣和能量依赖性蛋白酶组成免受损坏。线粒体拥有每个应激诱导伴侣家族的代表性成员；因此，提供一个范例来阐明分子伴侣整体在蛋白质稳态中的功能维护。人们普遍认为分子伴侣提供了针对蛋白质的第一道防线通过促进正确折叠并防止异常折叠和聚集来防止错误折叠。线粒体伴侣蛋白也在大多数肿瘤细胞类型中广泛表达，包括结直肠癌、乳腺癌、前列腺癌和卵巢癌的死亡率最高，这表明线粒体伴侣在癌细胞的永生化并强调它们作为有前途的抗癌药物靶点的重要性。广泛而长期的研究目标是提供分子上的理解线粒体如何伴侣分子在生理条件下维持蛋白质稳态以及它们的功能如何在生理条件下调节病理状态。具体来说，我们将重点关注新型 ATP 依赖性线粒体的结构分析使用 X 射线晶体学和冷冻电镜的伴侣，使用功能确定其蛋白质相互作用组蛋白质组学，并使用结构引导的诱变方法来阐明其体外和体内的生物学功能活细胞。使用不同分辨率的多管齐下方法解决重要的生物医学问题时间尺度强调了拟议研究的重要性和影响。