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

基本信息

批准号：
9220839
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
项目类别：
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/9220839
关键词：
ATP phosphohydrolase Aging Alzheimer&apos s Disease Antineoplastic Agents Apoptosis Atherosclerosis Biochemical Cardiovascular Diseases Cell Survival Cells Cervix carcinoma Client Colon Carcinoma Colorectal Cancer Complex Crystallization Development Disease Down-Regulation Drug Targeting Functional disorder Goals Hand 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 Molecular Conformation Monitor Neoplasms Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Nuclear Nucleotides Organelles Parkinson Disease Pathologic Peptide Hydrolases Physiological Processes Population Process Proliferating Proteins Public Health Quality Control Research Resolution Role STAT3 gene Signal Transduction Structure Substrate Interaction System Testing Time Factors 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 proteostasis public health relevance small molecule surveillance strategy three dimensional structure transcription factor tumor

项目摘要

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，经测试，线粒体已经进化。同时，针对线粒体蛋白并选择性诱导细胞凋亡的因子（例如癌细胞）也受到积极的追捧，线粒体为阐明线粒体蛋白提供了范例。分子伴侣和能量依赖性蛋白酶网络，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和防止异常折叠和蛋白质聚集，提供了对抗蛋白质错误折叠疾病的第一道防线。除了在蛋白质折叠中发挥作用外，线粒体伴侣，例如 Mortalin (mtHsp70) 和 TRAP1 (mtHsp90) TRAP1 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，但在高度增殖的非肿瘤细胞中却没有显着表达。值得注意的是，TRAP1 的下调会消除转化。骨肉瘤、结肠癌和宫颈癌细胞的潜力，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。细胞，强调线粒体伴侣作为有前途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，以确定潜在的合作机制和功能。正常和病理状态下的线粒体蛋白质折叠机制，以及如何使用小分子调节线粒体伴侣功能本研究的目标将通过以下具体目标来实现：1）表征正常和病理状态下的线粒体蛋白质折叠机制。疾病状态；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 与底物相互作用的结构和分子基础。体外和体内方法，跨越不同的分辨率尺度并增加了拟议研究的创新。