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.

 描述（申请人提供）：线粒体变性和功能障碍是衰老和与衰老相关的人类疾病的标志，包括阿尔茨海默病、帕金森病、亨廷顿病、癌症、2型糖尿病、动脉粥样硬化和心血管疾病。因此，线粒体进化出了多种监视策略来保护细胞器免受损害。与此同时，人们正在积极寻找靶向线粒体蛋白并选择性诱导细胞凋亡（例如癌细胞）的因子。线粒体提供了一个阐明分子伴侣和能量依赖性蛋白酶网络的范例，它们协同作用以维持线粒体基质中的蛋白质稳态。人们普遍认为，分子伴侣通过促进折叠并防止异常折叠和蛋白质聚集，提供了针对蛋白质错误折叠疾病的第一道防线。除了在蛋白质折叠中的作用外，线粒体伴侣，如 Mortalin (mtHsp70) 和 TRAP1 (mtHsp90) 也在大多数肿瘤细胞类型中广泛表达，包括结直肠癌、乳腺癌、前列腺癌和卵巢癌，这些细胞的死亡率最高，但引人注目的是不在高度增殖的非肿瘤细胞中表达。值得注意的是，TRAP1 的下调消除了骨肉瘤、结肠癌和宫颈癌细胞的转化潜力，支持线粒体伴侣在癌细胞永生化中的新作用。一致地，抑制 TRAP1 会诱导前列腺癌细胞凋亡，这强调了线粒体伴侣作为有希望的新药物靶点的重要性。广泛而长期的研究目标是提供对体外和体内线粒体蛋白质质量控​​制系统的分子理解，确定正常和病理状态下线粒体蛋白质折叠机制的潜在合作机制和功能，以及如何使用小分子调节线粒体伴侣功能。这项研究的目标将通过以下具体目标来实现：1）表征正常和疾病状态下的线粒体蛋白质折叠机制； 2）用小分子化合物靶向TRAP1的结构来调节其伴侣功能； 3) 确定 TRAP1-底物相互作用的结构和分子基础。为了实现我们的研究目标，我们将采用多管齐下的体外和体内方法，跨越不同的分辨率尺度，并增加拟议研究的创新性。