Yeast Ess1, a Conserved PPlase Essential for Mitosis

酵母 Ess1，有丝分裂必需的保守 Pplase

• 批准号: 7379910
• 负责人: Steven D. HANES
• 金额: $ 29.62万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7379910
• 关键词: Affect; Antifungal Agents; Binding; Biochemical; Candida albicans; Cell Cycle Regulation; Cell physiology; Cells; Chromatin; Class; 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; Localized; Malignant Neoplasms; Messenger RNA; Mitosis; Mitotic; Modification; Molecular; Multiprotein Complexes; Muscle Rigidity; Mycoses; Neurodegenerative Disorders; Object Attachment; Organism; Pathway interactions; Patients; Peptides; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Phosphorylation; Play; Polymerase; Process; Proline; Proteins; Public Health; 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

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 - 蛋白酶异构酶（PPIASES）如何控制重要的细胞过程，例如转录和有丝分裂。 PPIAS催化肽键的顺式/反式异构化，该肽键在环状氨基酸脯氨酸之前。脯氨酰 - 异构化会导致构象变化，影响新合成蛋白的折叠并调节成熟蛋白的活性。 PPIAS在所有生物体中都发现，并且最著名，因为它们是免疫抑制药物的靶标。但是，它们在细胞中的正常功能在某种程度上是很众所周知的，因为大多数可以通过其各自生物体中的基因缺失去除，而不会可观察到的后果。一个名为ESS1的PPIASE是一个例外，这对于酵母菌的生长至关重要。 ESS1及其人类同源物PIN1与转录调控和细胞周期控制有关。 ESS1与RNA聚合酶II的大亚基的羧基末端结构域（CTD）在物理和遗传上相互作用。提议ESS1使CTD异构化，从而控制多个转录和mRNA处理的多个离散阶段之间的过渡。 ESS1的丧失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。这项研究将着重于确定ESS1控制转录及其对全球基因表达的重要性的机制。它还将探索靶向ESS1在致病酵母中靶向临床应用的结构基础。具体而言，目的是：（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研究与肾小球构成的长期依从性依次的依从性的肾上腺素的依从性，并将其依赖的肾上腺均匀键合中的依次分析，用于开发抗真菌药物。公共卫生相关性：真菌中ESS1的研究对于我们对人类对应物PIN1的理解非常重要，PIN1与癌症和神经退行性疾病有关。结果还可以建立ESS1作为治疗威胁生命真菌感染患者的新药物。