Phosphoserine Dependant Assembly of Signaling complexes

信号复合物的磷酸丝氨酸依赖性组装

• 批准号: 6826479
• 负责人: MICHAEL B YAFFE
• 金额: $ 30.22万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826479
• 关键词: DNA damage; biological signal transduction; combinatorial chemistry; enzyme activity; functional /structural genomics; ligands; peptide library; phosphorylation; phosphoserine; protein binding; protein kinase; protein sequence; structural biology

DESCRIPTION (provided by applicant): Phosphoserine/threonine-binding domains play critical roles in controlling multiple aspects of cell proliferation, including cell cycle progression and the cellular response to DNA damage. The current list of pSer/pThr-binding domains includes 14-3-3 proteins, FHA domains, WW domains, WD40 repeats of F-box proteins, tandem BRCT domains and the Polo-box domains of Polo-like kinases. The long-term goal of our laboratory is to identify and characterize these domains with a focus on identifying their physiological ligands, determining the structural basis for their pSer/Thr-motif recognition, and elucidating the molecular basis for their functions in cell cycle control within complex protein kinase signaling networks. Polo-like kinases are essential during multiple stages of the eukaryotic cell cycle, including many of the events that occur during M-phase, as well as in the DNA damage response. Despite their importance, details about how Polo-like kinase activity is regulated, and the identity of their substrates are poorly understood. In this proposal we use a combination of biochemical, structural and cell biological techniques to determine the function of the invariant pSer/pThr-binding Polo-box domain in regulating the activation of, and the substrate selection and phosphorylation by Polo-like kinases. In the process, we will identify many new Polo-like kinase ligands and substrates that may be responsible for the pleiotropic role these kinases play in the cell. Since Polo-like kinases are upregulated in many types of human cancer, and since their experimental down-regulation results in decreased cell proliferation and tumor regression, the results of our experiments should determine whether the Polo-box domain is a good target for novel anti-cancer drug design.

描述（由申请人提供）： 磷酸丝氨酸/苏氨酸结合结构域在控制细胞增殖的多个方面发挥关键作用，包括细胞周期进程和细胞对DNA损伤的反应。目前pSer/pThr结合结构域的列表包括14-3-3蛋白、FHA结构域、WW结构域、F-box蛋白的WD 40重复序列、串联BRCT结构域和Polo样激酶的Polo-box结构域。我们实验室的长期目标是识别和表征这些结构域，重点是识别其生理配体，确定其pSer/Thr基序识别的结构基础，并阐明其在复杂蛋白激酶信号网络中细胞周期控制功能的分子基础。Polo样激酶在真核细胞周期的多个阶段是必不可少的，包括在M期发生的许多事件，以及在DNA损伤反应中。尽管它们的重要性，Polo样激酶活性是如何调节的细节，以及它们的底物的身份知之甚少。在这个建议中，我们使用的生物化学，结构和细胞生物学技术的组合，以确定的功能不变的pSer/pThr结合Polo盒域在调节激活，底物选择和磷酸化的Polo样激酶。在这个过程中，我们将确定许多新的Polo样激酶配体和底物，可能是负责这些激酶在细胞中发挥的多效性作用。由于Polo样激酶在许多类型的人类癌症中上调，并且由于它们的实验下调导致细胞增殖减少和肿瘤消退，因此我们的实验结果应该确定Polo框结构域是否是新型抗癌药物设计的良好靶标。