Structure, Function, and Mechanism of a Mitochondrial Chaperone

线粒体伴侣的结构、功能和机制

• 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
• 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' 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

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.

总结 线粒体是细胞的动力源，对细胞和生物体的健康至关重要。 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、亨廷顿舞蹈病 疾病、癌症、动脉粥样硬化和心血管疾病。因此，几种监视策略 已经进化出由分子伴侣和保护线粒体的能量依赖性蛋白酶组成 免受伤害线粒体具有每个应激诱导型伴侣蛋白家族的代表性成员;因此， 为阐明分子伴侣在蛋白质稳定中的整体功能提供了一个范例 上维护人们普遍认为，分子伴侣提供了针对蛋白质的第一道防线， 通过促进正确折叠和防止异常折叠和聚集来防止错误折叠。线粒体 分子伴侣还在大多数肿瘤细胞类型中广泛表达，包括结肠直肠、乳腺、前列腺和乳腺癌。 卵巢癌，其中有最高的死亡率，表明线粒体伴侣蛋白的核心作用， 癌细胞的永生化，并强调其作为有前途的抗癌药物靶点的重要性。 广泛和长期的研究目标是提供一个分子理解如何线粒体 分子伴侣在生理条件下维持蛋白质稳态，以及它们的功能如何被调节， 病理状态。具体来说，我们将集中在一个新的ATP依赖性线粒体的结构分析， 使用X射线晶体学和cryoEM，确定其蛋白质相互作用组，使用功能 蛋白质组学，并使用结构指导的诱变方法来阐明其在体外和体内的生物学功能。 活细胞采用多管齐下的方法以不同的分辨率解决一个重要的生物医学问题 和时间尺度强调了拟议研究的意义和影响。