Structure, Function, and Mechanism of a Mitochondrial Chaperone

线粒体伴侣的结构、功能和机制

• 批准号: 10493261
• 负责人: Francis T.F. Tsai
• 金额: $ 46.04万
• 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/10493261
• 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.

摘要 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，线粒体退化和功能障碍是人类疾病的特征，包括 发育和代谢障碍、2型糖尿病、阿尔茨海默病、帕金森病、亨廷顿病 疾病、癌症、动脉粥样硬化和心血管疾病。因此，有几种监视战略 已经进化出由分子伴侣和保护线粒体的能量依赖的蛋白酶组成 免受损害。线粒体拥有每个应激诱导伴侣蛋白家族的代表性成员；因此， 为阐明分子伴侣系统在蛋白平衡中的作用提供了一个范例 维修。人们普遍认识到，分子伴侣是抵御蛋白质的第一道防线。 通过促进正确的折叠和防止异常折叠和聚集来实现错误折叠。线粒体 伴侣蛋白在大多数肿瘤细胞类型中也广泛表达，包括结直肠、乳腺、前列腺和 死亡率最高的卵巢癌，表明线粒体伴侣在卵巢癌中的核心作用 癌症细胞的永生化，并强调它们作为有希望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线粒体是如何 伴侣蛋白在生理条件下维持蛋白稳定，以及它们的功能是如何在 病态。具体地说，我们将集中在一种新的依赖于ATP的线粒体的结构分析上 用X射线结晶学和低温电子显微镜确定其蛋白质相互作用组 蛋白质组学，并使用结构导向的突变方法来阐明其在体外和在 活细胞。使用不同分辨率的多管齐下的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意义和影响。