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.

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