Structure, Function, and Mechanism of a Mitochondrial Chaperone

线粒体伴侣的结构、功能和机制

• 批准号: 10663341
• 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/10663341
• 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; 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; 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.

概括 线粒体充当细胞的动力室，对于细胞和有机体健康至关重要。 相反，线粒体变性和功能障碍是人类疾病的标志 发育和代谢疾病，2型糖尿病，阿尔茨海默氏病，帕金森氏病，亨廷顿 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，由分子伴侣和能量依赖性蛋白酶组成，这些蛋白酶保护线粒体 受损害。线粒体具有每个应力诱导的伴侣家族的代表成员；因此， 提供范式来阐明分子伴侣在蛋白质的功能 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 通过促进正确的折叠并防止异常折叠和聚集来折叠。线粒体 伴侣在大多数肿瘤细胞类型中也广泛表达，包括大肠，乳房，前列腺和 卵巢癌的死亡率最高，表明线粒体伴侣在中心作用 癌细胞的永生化并强调了它们作为有希望的抗癌药物靶标的意义。 广泛的长期研究目标是提供分子理解线粒体的理解 伴侣在生理条件下维持蛋白质量以及如何调节其功能 病理状态。具体而言，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在体外阐明其生物学功能 活细胞。使用以不同分辨率的多管制方法来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。

项目成果

Second Virtual International Symposium on Cellular and Organismal Stress Responses, September 8-9, 2022.

• DOI: 10.1007/s12192-022-01318-5
• 发表时间: 2023-01
• 期刊: CELL STRESS & CHAPERONES
• 影响因子: 3.8
• 作者: van Oosten-Hawle, Patricija;Backe, Sarah J.;Ben-Zvi, Anat;Bourboulia, Dimitra;Brancaccio, Mara;Brodsky, Jeff;Clark, Melody;Colombo, Giorgio;Cox, Marc B.;de los Rios, Paolo;Echtenkamp, Frank;Edkins, Adrienne;Freeman, Brian;Goloubinoff, Pierre;Houry, Walid;Johnson, Jill;LaPointe, Paul;Li, Wei;Mezger, Valerie;Neckers, Len;Nillegoda, Nadinath B.;Prahlad, Veena;Reitzel, Adam;Scherz-Shouval, Ruth;Sistonen, Lea;Tsai, Francis T. F.;Woodford, Mark R.;Mollapour, Mehdi;Truman, Andrew W.
• 通讯作者: Truman, Andrew W.