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Clk Kinases and Splicing Regulation

Clk 激酶和剪接调节

基本信息

批准号：
9356568
负责人：
JOSEPH ADAMS
金额：
$ 31.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9356568
关键词：
3&apos Splice Site Active Sites Affect Alzheimer&apos s Disease Ataxia Binding Biochemical Biological Biological Assay Biological Process C-terminal Cell Nucleus Cell Survival Cell physiology Cells Chemicals Complex Data Development Dipeptides Disease Docking Enzymes Event Family Funding Genes Genomics Goals Growth and Development function Health Human Image In Vitro Link Macromolecular Complexes Malignant Neoplasms Mediator of activation protein Mental disorders Messenger RNA Methods Modification Molecular Conformation Muscular Dystrophies N-terminal Nature Nuclear Parkinsonian Disorders Pattern Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Protein Conformation Protein Family Protein Kinase Protein phosphatase Proteins RNA Splicing RRM1 gene RRM2 gene Regulation Role STY kinase Site Specificity Spliced Genes Spliceosomes Structure U1 Small Nuclear Ribonucleoprotein acrosome stabilizing factor biophysical techniques experimental study genome-wide human disease in vivo prolyl-serine public health relevance scaffold seryl-proline

项目摘要

Project Summary/Abstract: While the proper selection of splice sites drives genomic diversity, adaptive growth and development, errors in splicing can have enormous detrimental effects on function and is now recognized as the underlying cause for many human diseases. Indeed, splicing errors are associated with muscular dystrophy, Alzheimer's disease, Parkinsonism, psychiatric disorders, ataxias and cancers making the study of factors that control splice-site selection vitally important for human health. Splicing occurs at the spliceosome, a macromolecular complex composed of several RNAs and numerous proteins. Critical to normal gene splicing is the proper selection of the 5'-3' splice sites, events that occur early in the development of the spliceosome and whose specificity is guided by an essential family of splicing factors known as SR proteins. The phosphorylation states of SR proteins directly impact their subcellular localization and splicing activities but our understanding of how these different forms are attained is, at best, incomplete. The CLK family of protein kinases phosphorylates SR proteins and mobilizes them to sites of active gene splicing. The CLKs differ from many classic protein kinases in that they lack a docking groove for substrate binding but instead contain a disordered N-terminal extension that we showed attaches to the SR protein. In this proposal we will explore the role of the N-terminus for the mobilization of CLK1 and recognition of SR proteins in the nucleus using a wide array of in vivo and in vitro experiments. We will study the effects of CLK-dependent phosphorylation on SR protein conformation, subcellular localization, and interactions with critical mediators of splice-site selection in the spliceosome. The larger goal of this proposal is to define CLK function at both biological and biochemical levels so that we can better understand the mechanisms of human diseases associated with errors in splicing.

项目总结/文摘: