Yeast Ess1, a Conserved PPlase Essential for Mitosis

酵母 Ess1，有丝分裂必需的保守 Pplase

• 批准号: 7786254
• 负责人: Steven D. HANES
• 金额: $ 15.27万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2011-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7786254
• 关键词: Affect; Antifungal Agents; Binding; Biochemical; Candida albicans; Cell Cycle Regulation; Cell physiology; Cells; Chromatin; Complex; Cyclic Amino Acids; Defect; Development; Drug Delivery Systems; Enzymes; Gene Deletion; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Homologous Gene; Human; Immunosuppressive Agents; In Vitro; Life; Malignant Neoplasms; Messenger RNA; Mitosis; Mitotic; Modification; Molecular; Multiprotein Complexes; Muscle Rigidity; Mycoses; Neurodegenerative Disorders; Organism; Pathway interactions; Patients; Peptides; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Phosphorylation; Play; Polymerase; Process; Proline; Proteins; RNA Polymerase II; RNA polymerase II largest subunit; Role; Running; Saccharomyces cerevisiae; Screening procedure; Staging; Stress; Structure; Substrate Interaction; Synthetic Genes; Transcriptional Regulation; Virulence; Work; Yeasts; base; cdc Genes; cis trans isomerization; clinical application; enzyme activity; enzyme substrate; fungus; in vivo; mutant; parvulin; public health relevance

DESCRIPTION (provided by applicant): The long-term goal is to understand how peptidyl-prolyl isomerases (PPIases) control important cellular processes such as transcription and mitosis. PPIases catalyze the cis/trans isomerization of the peptide bond that precedes the cyclic amino acid proline. Prolyl-isomerization results in conformational changes that affect the folding of newly synthesized proteins and regulates the activity of mature proteins. PPIases are found in all organisms, and are best known because they are the targets of immunosuppressive drugs. However, their normal function in cells is poorly understood, in part, because most can be removed by gene deletion in their respective organism without observable consequences. One exception is a PPIase called Ess1, which is essential for growth in the yeast, Saccharomyces cerevisiae. Ess1 and its human homolog, Pin1, are implicated in transcription regulation and cell cycle control. Ess1 interacts physically and genetically with the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II. Ess1 is proposed to isomerize the CTD and thereby control the transition between multiple, discrete stages of transcription and mRNA processing. Loss of Ess1 causes cells to undergo mitotic arrest, perhaps due to defects in transcription of key cell cycle genes. This study will focus on determining the mechanism by which Ess1 controls transcription and its importance for global gene expression. It will also explore the structural basis for targeting of Ess1 in pathogenic yeast for clinical applications. Specifically, the aims are to: (1) Use biochemical and molecular approaches to determine the mechanism by which Ess1 regulates RNA polymerase II activity, (2) Use genetic and genomic approaches to identify genes that require Ess1, (3) Use structure and function analysis to examine enzyme-substrate interactions by Candida albicans Ess1, with the long-term goal of exploiting key differences between the fungal and human enzymes for development of antifungal drugs. Public Health Relevance: The study of Ess1 in fungi will be important for our understanding of the human counterpart, Pin1, which has been associated with cancers and neurodegenerative disorders. The results may also establish Ess1 as a new drug target for treatment of patients with life- threatening fungal infections.

描述（由申请人提供）：长期目标是了解肽基脯氨酰异构酶（PPIase）如何控制重要的细胞过程，例如转录和有丝分裂。 PPI酶催化环状氨基酸脯氨酸之前的肽键的顺式/反式异构化。脯氨酰异构化导致构象变化，影响新合成蛋白质的折叠并调节成熟蛋白质的活性。 PPI酶存在于所有生物体中，并且因其是免疫抑制药物的靶标而最为人所知。然而，人们对它们在细胞中的正常功能知之甚少，部分原因是大多数可以通过各自生物体中的基因删除而被去除，而不会产生可观察到的后果。一个例外是一种名为 Ess1 的 PPI 酶，它对于酿酒酵母的生长至关重要。 Ess1 及其人类同源物 Pin1 参与转录调控和细胞周期控制。 Ess1 在物理和遗传上与 RNA 聚合酶 II 大亚基的羧基末端结构域 (CTD) 相互作用。 Ess1 被认为可以使 CTD 异构化，从而控制转录和 mRNA 加工的多个离散阶段之间的过渡。 Ess1 的缺失会导致细胞发生有丝分裂停滞，这可能是由于关键细胞周期基因的转录缺陷所致。这项研究将重点确定 Ess1 控制转录的机制及其对全局基因表达的重要性。它还将探索在临床应用中靶向致病性酵母中 Ess1 的结构基础。具体来说，目标是：(1) 使用生化和分子方法来确定 Ess1 调节 RNA 聚合酶 II 活性的机制，(2) 使用遗传和基因组方法来识别需要 Ess1 的基因，(3) 使用结构和功能分析来检查白色念珠菌 Ess1 的酶-底物相互作用，长期目标是利用真菌和人类酶之间的关键差异 用于开发抗真菌药物。公共健康相关性：真菌中 Ess1 的研究对于我们了解人类对应的 Pin1 非常重要，Pin1 与癌症和神经退行性疾病有关。该结果还可能将 Ess1 确立为治疗危及生命的真菌感染患者的新药物靶点。