Structural Biology Studies of Ribosome Biogenesis Network

描述：核糖体是进化上保守的分子机器 用来合成蛋白质。在真核细胞中，核糖体是在生物物理学中产生的 独特的亚核隔间，即核仁，通过能量驱动的级联 事件。这一过程是许多遗传性疾病的基础，也是 抗癌和抗神经退行性变治疗药物。然而，物理相互作用 这一进程所需网络的大部分仍未确定特征。此应用程序 将描述一种名为R2TP的关键分子复合体，它在核糖体中起早期作用 通过促进几种核糖体生产酶的组装进行生产。R2TP具有 广泛的客户群，与一种常见的蛋白质折叠伴侣热休克合作 蛋白质90(Hsp90)，并将客户递送到核仁。LI实验室使用一个 结构生物学、生化和遗传学方法的结合提供了 R2TP的功能洞察及其对核糖体生产的影响。异常地 R2TP本身和R2TP操作的详细三维视图将在 并与可用的功能数据一起获得和分析。两个具体目标是 旨在1)建立R2TP的结构和功能循环；2)阐明R2TP的 R2TP的生理作用。这项研究的结果将确定新的分子位点 通过核糖体调控开发抗癌和抗神经退行性变药物 生产和退化。李实验室组建了一支科学家团队， 在X射线结晶学、高通量电子方面的互补专业知识 冷冻显微镜、质谱学、生物物理学、蛋白质生物化学和酵母 为了在降低风险的同时最大限度地增加成功的机会，我们必须从遗传学的角度出发。 相关性：核仁形态和功能的异常与癌症有关 和人类的阿尔茨海默氏症。相应地，R2TP及其客户蛋白具有 已被确定为核仁形态的关键调节因子。鉴于超过15个 已经对抗癌药物的类型进行了研究，或正在进行针对 参与这一途径的分子，没有一个是已知的抗神经退行性变的。尽管 在细胞死亡分析中有效，许多化合物的药理基础仍然是 一些细菌会在细胞中产生抗药性。拟议的研究提供了 在发现新药的同时解释现有药物的作用的平台。

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.