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: 8839001
• 负责人: Francis T.F. Tsai
• 金额: $ 38.07万
• 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/8839001
• 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; 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; novel therapeutics; osteosarcoma; paralogous gene; prevent; prostate cancer cell; protein aggregation; protein folding; protein misfolding; public health relevance; 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（由适用提供）：线粒体变性和功能障碍是衰老和与衰老有关的人类疾病的标志，包括阿尔茨海默氏病，帕金森病，帕金森病，亨廷顿疾病，癌症，2型糖尿病，动脉粥样硬化，动脉粥样硬化和心血管疾病。因此，线粒体发展了几种保护细胞器免受损害的监视策略。同时，靶向线粒体蛋白和选择性诱导凋亡的因素，例如癌细胞，在此之后受到积极伤害。线粒体提供了一个范式，以阐明分子链酮和能量依赖性蛋白的网络，该蛋白具有协同作用，可维持线粒体基质中的蛋白质稳态。人们普遍认为，分子链酮通过促进折叠并防止异常折叠和蛋白质聚集提供针对蛋白质错误折叠疾病的第一道防线。除了它们在蛋白质折叠中的作用外，线粒体伴侣（例如mortalin（MTHSP70）和TRAP1（MTHSP90））在大多数肿瘤细胞类型中也得到广泛表达，包括结直肠癌，乳腺癌，前列腺癌和卵巢癌，这些癌症的死亡率最高，但在高度增殖的非肥大细胞中，它们具有最高的含量。值得注意的是，TRAP1的下调消除了骨肉瘤，结肠癌和子宫颈癌细胞的转化潜力，从而支持了线粒体链在癌细胞免疫化中的新作用。一致地，抑制TRAP1会诱导前列腺癌细胞的凋亡，突显了线粒体链烷的重要性，这是有希望的新药物靶标。广泛的长期研究目标是在体外和体内对线粒体蛋白质质量控​​制系统提供分子理解，以确定正常和病理状态中线粒体蛋白折叠机制的潜在合作机制和功能，以及如何使用小分子来调节线粒体链酮链酮的功能。这项研究的目标将通过以下特定目的来实现：1）表征正常和疾病状态下的线粒体蛋白折叠机械； 2）用小分子化合物靶向TRAP1的结构，以调节其伴侣功能； 3）确定Trap1-Substrate相互作用的结构和分子基础。为了实现我们的研究目标，我们将使用一种多管齐下的体外和体内方法，该方法涵盖了不同的分辨率量表，并增加了拟议研究的创新。