Structural and Mechanistic Studies of the Mitochondrial Protein Folding Machinery

线粒体蛋白质折叠机制的结构和机制研究

• 批准号: 9024577
• 负责人: Francis T.F. Tsai
• 金额: $ 34.06万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9024577
• 关键词: ATP phosphohydrolase; Aging; Alzheimer' s Disease; Antineoplastic Agents; Apoptosis; Atherosclerosis; Binding; Biochemical; Cardiovascular Diseases; Cell Survival; Cells; Cervix carcinoma; Client; Colon Carcinoma; Colorectal Cancer; Complex; Development; Disease; Down-Regulation; Drug Targeting; Functional disorder; Goals; Hand; Health; Homeostasis; Homologous Gene; Human; Huntington Disease; Hybrids; In Vitro; Ligand Binding; Light; Malignant Epithelial Cell; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Metabolic Diseases; Methods; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Molecular; Molecular Chaperones; Monitor; Neoplasms; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nucleotides; Organelles; Parkinson Disease; Peptide Hydrolases; Physiological Processes; Population; Process; Proliferating; Proteins; Public Health; Quality Control; Research; Resolution; Role; STAT3 gene; Signal Transduction; Staging; Structure; Substrate Interaction; System; Testing; Time Factors; age related; base; cancer cell; cancer type; cell type; chaperone machinery; drug development; gambogic acid; human disease; in vivo; inhibitor/antagonist; innovation; interest; malignant breast neoplasm; member; mitochondrial dysfunction; mortalin; mortality; mutant; neoplastic cell; new therapeutic target; novel therapeutics; osteosarcoma; paralogous gene; prevent; prostate cancer cell; protein aggregation; protein folding; protein misfolding; small molecule; surveillance strategy; three dimensional structure; transcription factor; tumor

 DESCRIPTION (provided by applicant): Mitochondrial degeneration and dysfunction are a hallmark of aging and aging-related human diseases, including Alzheimer disease, Parkinson disease, Huntington disease, cancer, type 2 diabetes, atherosclerosis, and cardiovascular diseases. Consequently, mitochondria have evolved several surveillance strategies to protect the organelle from damage. At the same time, factors that target mitochondrial proteins and selectively induce apoptosis, for instance of cancer cells, are actively sought after. The mitochondria provide a paradigm to elucidate the network of molecular chaperones and energy-dependent proteases, which function synergistically to maintain protein homeostasis in the mitochondrial matrix. It is widely appreciated that molecular chaperones provide the first line of defense against protein misfolding diseases by promoting folding and preventing aberrant folding and protein aggregation. In addition to their role in protein folding, mitochondrial chaperones, such as Mortalin (mtHsp70) and TRAP1 (mtHsp90) are also widely expressed in most tumor cell types, including colorectal, breast, prostate, and ovarian cancer, which have the highest mortality rates, but strikingly not in highly proliferating, non-tumor cells. Remarkably, down- regulation of TRAP1 abrogates the transforming potential of osteosarcoma, colon carcinoma, and cervix carcinoma cells, supporting a new role of mitochondrial chaperones in the immortalization of cancer cells. Consistently, inhibition of TRAP1 induces apoptosis in prostate cancer cells, underscoring the significance of mitochondrial chaperones as promising new drug targets. The broad and long-term research objective is to provide a molecular understanding of the mitochondrial protein quality control system in vitro and in vivo, to determine the underlying cooperative mechanism and function of the mitochondrial protein folding machinery in normal and pathological states, and how small molecules can be used to modulate mitochondrial chaperone function. The goals of this research will be pursued through the following specific aims: 1) to characterize the mitochondrial protein folding machinery in normal and disease states; 2) to target the structure of TRAP1 with small molecule compounds to modulate its chaperone function; and 3) to determine the structural and molecular basis of TRAP1-substrate interaction. To accomplish our research objective, we will use a multi-pronged in vitro and in vivo approach, which spans different resolution scales and adds to the innovation of the proposed research.