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Molecular steps in TAO kinase regulation

TAO 激酶调节的分子步骤

基本信息

批准号：
10473664
负责人：
MELANIE H. COBB
金额：
$ 32.8万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473664
关键词：
Binding Binding Sites Biochemical Biochemical Process Biological Biological Assay Bypass Catalytic Domain Cell Nucleus Cells Chemicals Complex Crystallization Cytoplasm Disinhibition Dissociation Drug Targeting Elements Enzymes Event Exhibits Foundations Future In Vitro Knowledge Literature MAP Kinase Gene MAP Kinase Kinase Kinase Membrane Modeling Molecular Nature Pathologic Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Processes Positioning Attribute Protein Kinase Protein phosphatase Proteins RNA Processing Recombinants Regulation Reporting Schistosoma Serine Signal Transduction Specificity Structure Surface Therapeutic Virus Diseases Work base drug development drug discovery experience in vivo influenza infection inhibitor insight kinase inhibitor novel novel therapeutics p38 Mitogen Activated Protein Kinase protein complex reconstitution viral RNA

项目摘要

Despite their discovery over 20 years ago, TAO protein kinases (TAO1-3) remain understudied. In particular, we lack an understanding of the mechanisms regulating TAO activation, how they recognize substrates, and how these kinases contribute to key physiological processes. We originally identified TAOs through a large- scale effort to find membrane proximal components of MAPK cascades and showed that TAOs are MAP3Ks in the p38 pathway. Recent work now reveals that TAOs are essential for schistosome and viral infections and viral RNA processing and export from the nucleus. These findings suggest that TAOs are drug targets for a range of pathophysiological conditions and beg for a greater understanding of how their activities are controlled. Here, we propose to develop a paradigm for the biochemical regulation of TAO protein kinases through their integration with phosphoprotein phosphatase 1 (PP1). These results should advance future drug discovery efforts to provide new therapeutic entry points for treating a range of diverse pathological conditions. An obstacle in realizing their therapeutic potential is the limited knowledge of their regulation and partners. In searching for regulatory interactions, we found that TAOs directly bind PP1 and its R7 regulatory subunit. While PP1 dephosphorylates half the proteins in the cell, its activity is largely restricted within heteromeric complexes by regulatory subunits. Recent literature indicates that R7 maintains PP1 in an inactive state. We propose that TAOs modulate PP1 phosphatase activity via direct interactions and by R7 phosphorylation. The connection with PP1 offers TAOs wide opportunities to impact cellular control mechanisms. Our specific aims are to 1) determine how the TAO-PP1 complex regulates TAO activity; and 2) determine how TAO through R7 regulates PP1 activity. Biochemical and cell biological studies will take advantage of a model of a TAO2-PP1 complex based on our crystal structure of the TAO2 kinase domain that shows the PP1 binding motif on TAO. The relevance of this interaction is supported by our recent work revealing co-localization of TAO2 and PP1 in structures in the nucleus and the cytoplasm. Our extensive experience in identifying and characterizing TAOs, determining the structure of the TAO kinase domain, identifying chemically tractable inhibitors, and elucidating TAO-dependent pathways, since our discovery of these kinases, puts us in a unique position to determine biochemical processes that will provide a foundation for TAO kinases as subjects of drug development.

尽管在20多年前就发现了TAO蛋白激酶（TAO1-3），但对它的研究仍然不足。特别是，我们缺乏对调节TAO激活的机制的理解，它们如何识别底物，以及这些激酶如何参与关键的生理过程。我们最初通过大规模努力寻找MAPK级联的膜近端组分来确定TAOs，并表明TAOs是p38途径中的MAP3Ks。最近的研究表明，TAOs对血吸虫和病毒感染以及病毒RNA加工和从细胞核输出至关重要。这些发现表明，TAOs是一系列病理生理条件的药物靶点，并要求对其活动如何被控制有更深入的了解。在这里，我们建议通过TAO蛋白激酶与磷酸蛋白磷酸酶1 （PP1）的整合来开发生化调节的范例。这些结果将推动未来的药物发现工作，为治疗一系列不同的病理状况提供新的治疗切入点。实现其治疗潜力的一个障碍是对其调节和合作伙伴的知识有限。在寻找调控相互作用时，我们发现TAOs直接结合PP1及其R7调控亚基。