Maturation of the Large Ribosomal Subunit in Yeast

酵母大核糖体亚基的成熟

• 批准号: 7933112
• 负责人: Arlen W JOHNSON
• 金额: $ 12.94万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933112
• 关键词: Accounting; Address; Aden; Amino Acid Motifs; Animal Model; Binding; Binding Proteins; Biochemical; Biochemical Genetics; Biogenesis; Biological Assay; Cell Nucleus; Cell Proliferation; Cells; Complex; Coupled; Cytoplasm; Data; Defect; Development; Disease; Energy Metabolism; Ensure; Event; Genetic; Genetic Code; Genetic Screening; Genetic screening method; Grant; Growth and Development function; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; Mediating; Metabolic; Modeling; Molecular; Normal Cell; Nuclear Export; Pathway interactions; Pharmaceutical Preparations; Process; Protein Biosynthesis; Proteins; Publishing; RNA, ribosomal, 26S; Reagent; Recycling; Regulation; Research Personnel; Ribosomal Proteins; Ribosomal RNA; Ribosomes; Signal Transduction; Testing; Translating; Translation Initiation; Translations; Up-Regulation; Work; Yeasts; Zinc Fingers; adapter protein; base; cell growth; cellular targeting; human PRDX1 protein; in vitro Assay; in vitro activity; in vivo; insight; methionyl aminopeptidase; mutant; polypeptide; premature; programs; protein function; receptor; reconstitution; research study; tool

DESCRIPTION (provided by applicant): The ribosome is responsible for protein synthesis and is essential in all cells. Its faithful translation of the genetic code and the proper regulation of its activity are necessary for normal cell growth and development. Ribosome assembly is a complex and dynamic process and mechanisms must exist that ensure the correct assembly of ribosomes in order to maintain the fidelity of translation. In addition, ribosome biogenesis accounts for a large portion of the energy expenditure of a rapidly dividing cell and must be coordinated with the metabolic needs of a cell. Indeed, cell proliferation in humans requires upregulation of ribosome biogenesis. Thus, understanding the mechanisms regulating ribosome biogenesis will provide insight for the development of new tools for controlling cell proliferation in disease states. The delineation of fundamental cellular pathways such as ribosome biogenesis and translation is also necessary for the intelligent development of new drugs that are specific to their intended cellular targets without impinging on other cellular pathways. We recently identified the nuclear export pathway for the large ribosomal subunit in yeast. We showed that its export depends on the export adapter protein Nmd3p and the export receptor Crm1 and that this export pathway is conserved in human cells. In this proposal, we will expand on these initial findings using reagents that we have developed in our studies of NmdSp. This proposal will: 1) Address how the export adapter and its receptor assemble on the large ribosomal subunit to mediate export. 2) Elucidate the events required to release the export adapter from the subunit after delivery to the cytoplasm. 3) Determine the function of Arx1 p and Reilp, two functionally related proteins that act at the polypeptide exit tunnel on the nascent large ribosomal subunit during export and as it enters the cytoplasmic pool of active subunits.

描述（由申请人提供）：核糖体负责蛋白质合成，并且在所有细胞中都是必需的。它对遗传密码的忠实翻译及其活性的适当调节对于正常细胞生长和发育是必要的。核糖体组装是一个复杂且动态的过程，必须存在确保核糖体正确组装的机制，以维持翻译的保真度。此外，核糖体生物合成占快速分裂细胞能量消耗的很大一部分，并且必须与细胞的代谢需求相协调。事实上，人类细胞增殖需要核糖体生物发生的上调。因此，了解调节核糖体生物发生的机制将为开发用于控制疾病状态下细胞增殖的新工具提供见解。核糖体生物合成和翻译等基本细胞途径的描述对于智能开发新药也是必要的，这些新药专门针对其预期的细胞靶点而不影响其他细胞途径。我们最近确定了酵母中大核糖体亚基的核输出途径。我们表明，其输出依赖于输出接头蛋白 Nmd3p 和输出受体 Crm1，并且该输出途径在人类细胞中是保守的。在本提案中，我们将使用我们在 NmdSp 研究中开发的试剂来扩展这些初步发现。该提案将： 1) 解决输出接头及其受体如何在大核糖体亚基上组装以介导输出。 2) 阐明在递送至细胞质后从亚基释放输出接头所需的事件。 3) 确定 Arx1 p 和 Reilp 的功能，这两种功能相关的蛋白质在输出过程中以及进入活性亚基的细胞质池时在新生大核糖体亚基的多肽出口通道上发挥作用。