Yeast Ess1, a Conserved PPlase Essential for Mitosis

酵母 Ess1，有丝分裂所必需的保守 Pplase

• 批准号: 7901853
• 负责人: Steven D. HANES
• 金额: $ 18.74万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901853
• 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）：长期目标是了解肽酰脯氨酸异构酶（PPIases）如何控制重要的细胞过程，如转录和有丝分裂。PPIases催化在环氨基酸脯氨酸之前的肽键的顺/反异构化。脯氨酸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。PPIases存在于所有生物体中，因为它们是免疫抑制药物的靶点而为人所知。然而，人们对它们在细胞中的正常功能知之甚少，部分原因是它们中的大多数可以通过在各自的生物体中删除基因而不产生可观察到的后果。一个例外是一种名为Ess1的PPIase，它对酵母（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与RNA聚合酶II大亚基的羧基末端结构域（CTD）发生物理和遗传相互作用。Ess1被认为可以异构化CTD，从而控制转录和mRNA加工的多个离散阶段之间的过渡。Ess1的缺失导致细胞经历有丝分裂阻滞，这可能是由于关键细胞周期基因的转录缺陷。本研究将集中于确定Ess1控制转录的机制及其对全球基因表达的重要性。探索Ess1在病原菌中靶向的结构基础，为临床应用奠定基础。具体而言，目标是：(1)使用生化和分子方法确定Ess1调节RNA聚合酶II活性的机制；(2)使用遗传学和基因组学方法鉴定需要Ess1的基因；(3)使用结构和功能分析来检测白色念珠菌Ess1酶与底物的相互作用，长期目标是利用真菌和人类酶之间的关键差异开发抗真菌药物。公共卫生相关性：真菌中Ess1的研究将对我们理解人类对应的Pin1具有重要意义，Pin1与癌症和神经退行性疾病有关。这一结果也可能使Ess1成为治疗危及生命的真菌感染患者的新药物靶点。