Structural Biology Studies of Ribosome Biogenesis Network

核糖体生物发生网络的结构生物学研究

基本信息

批准号：
10389719
负责人：
Hong Li
金额：
$ 1.73万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389719
关键词：
3-Dimensional Alzheimer&apos s Disease Antineoplastic Agents Biochemical Biochemical Genetics Biogenesis Biological Assay Biophysics Cell Death Cell Nucleolus Cells Client Clinical Trials Complex Cryoelectron Microscopy Data Disease Enzymes Eukaryotic Cell Event Genetic Diseases Heat-Shock Proteins 90 Human Laboratories Link Malignant Neoplasms Mass Spectrum Analysis Methods Molecular Molecular Chaperones Molecular Machines Morphology Nerve Degeneration Pathway interactions Pharmaceutical Preparations Pharmacology Physiological Process Production Protein Biochemistry Protein Biosynthesis Proteins Research Resistance development Ribosomes Risk Role Scientist Structure Therapeutic X-Ray Crystallography anti-cancer base biophysical techniques design drug action insight molecular site protein folding structural biology success yeast genetics

项目摘要

Description: Ribosome is the evolutionarily conserved molecular machine responsible for synthesis of proteins. In eukaryotic cells, ribosome is produced in a biophysically distinct subnuclear compartment, the nucleolus, through a cascade of energy-driven events. This process underlies a number of genetic diseases and is a major target for anti-cancer and anti-neurodegeneration therapeutics. However, the physical interactions of the network required for this process remain largely uncharacterized. This application will characterize a key molecular complex called R2TP that acts early in ribosome production by facilitating assembly of several ribosome production enzymes. R2TP has a wide client base, collaborates with a general protein folding chaperone, heat shock protein 90 (Hsp90), and delivers clients to the nucleolus. The Li laboratory uses a combination of structural biology, biochemical, and genetics methods to provide functional insights on R2TP and its impact on ribosome production. Exceptionally detailed three-dimensional views of R2TP itself and those R2TP acts upon will be obtained and analyzed along with the available functional data. Two specific aims are designed to 1) establish the structure and function cycle of R2TP; 2) elucidate the physiological role of R2TP. Results of this study will identify new molecular sites for developing anti-cancer and anti-neurodegenerative drugs through controls of ribosome production and degradation. The Li laboratory has assembled a team of scientists with complementary expertise in x-ray crystallography, high-throughput electron cryomicroscopy, mass spectrometry, biophysics, protein biochemistry, and yeast genetics in order to maximize the chance of successes while mitigating risks. Relevance: Aberrant nucleolar morphology and function have been linked to cancers and Alzheimer's disease in human. Correspondingly, R2TP and its client proteins have been identified as key regulators of nucleolar morphology. Whereas more than fifteen types of anti-cancer drugs have been investigated or in clinical trials that target molecules involved in this pathway, none is known for anti-neurodegeneracy. Though effective in cell-death assays, the pharmacological basis of many compounds remains to be explained and some develop resistance in cells. The proposed research provides platforms for explaining the actions of the existing drugs while discovering new ones.

描述：核糖体是进化保守的分子机负责用于蛋白质的合成。在真核细胞中，核糖体是在生物物理中产生的通过级联的能量驱动的不同的亚核室，核仁事件。这个过程是许多遗传疾病的基础，是抗癌和抗神经变性疗法。但是，物理互动此过程所需的网络在很大程度上没有表征。此应用程序将表征一个称为R2TP的关键分子复合物，该复合物在核糖体早期起作用通过促进几种核糖体生产酶的组装生产。 R2TP具有一个广泛的客户群，与一般蛋白质折叠伴侣合作，热冲击蛋白质90（HSP90），并将客户提供给核仁。 Li实验室使用结构生物学，生化和遗传学方法的结合 R2TP的功能见解及其对核糖体产生的影响。异常 R2TP本身的详细三维观点，以及R2TP的行为将是与可用功能数据一起获得并分析。两个具体目标是设计为1）建立R2TP的结构和功能周期； 2）阐明 R2TP的生理作用。这项研究的结果将确定新的分子位点通过控制核糖体的控制，开发抗癌和抗神经退行性药物生产和退化。 LI实验室已经与 X射线晶体学，高通量电子的互补专业知识冷冻显微镜，质谱，生物物理学，蛋白质生物化学和酵母菌遗传学是为了在减轻风险的同时最大化成功的机会。相关性：异常的核仁形态和功能已与癌症联系起来和人类的阿尔茨海默氏病。相应地，R2TP及其客户端蛋白具有被确定为核仁形态的关键调节剂。而十五多个已经研究了抗癌药物的类型或在临床试验中参与该途径的分子，没有一个以抗神经退行性而闻名。尽管在细胞死亡测定中有效，许多化合物的药理基础仍然存在可以解释并有些在细胞中产生抗性。拟议的研究提供了在发现新药物时解释现有药物的作用的平台。