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Clk Kinases and Splicing Regulation

Clk 激酶和剪接调节

基本信息

批准号：
8638029
负责人：
JOSEPH ADAMS
金额：
$ 29.45万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638029
关键词：
3&apos Splice Site Address Affect Alternative Splicing Alzheimer&apos s Disease Applications Grants Arginine Ataxia Biological Assay Biological Process C-terminal Cells Data Development Dipeptides Disease Docking Enzymes Event Excision Family Genes Genome Genomics Growth and Development function Investigation Length Link Macromolecular Complexes Malignant Neoplasms Maps Mental disorders Messenger RNA Metabolic Diseases Modeling Muscular Dystrophies N-terminal Names Neurodegenerative Disorders Nuclear Nuclear Protein Parkinsonian Disorders Pattern Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Processed Genes Proline Protein Kinase Protein Splicing Proteins Proteome RNA RNA Splicing Regulation Reporter Genes Role STY kinase Sea Series Serine Site Source Specificity Spliced Genes Spliceosomes Structure Substrate Domain Substrate Specificity Techniques Testing Tissues acrosome stabilizing factor base human disease inorganic phosphate novel protein function prototype seryl-proline

项目摘要

DESCRIPTION (provided by applicant): While the proper selection of splice sites is essential for genomic diversity, adaptive growth and development, errors in splicing can have enormous detrimental effects on function and are 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 disease. 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' and 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 understandig of how these different forms are attained is, at best, incomplete. SR protein nuclear entry and splicing function are driven by a basal level of phosphorylation (hypo-phosphorylation) catalyzed by the SRPK family of protein kinases. However, this simple paradigm of one kinase-one substrate is now being challenged as a second protein kinase family has emerged as critical SR protein regulators. The Clk family of kinases can increase SR protein phosphoryl content to a greater extent than the SRPKs, generating hyper-phosphorylated forms that are largely uncharacterized at both structural and functional levels. While they differ substantially from the SRPKs in several ways, most importantly, Clk kinases possess an additional noncatalytic domain that we showed recently is responsible for its unique hyper-phosphorylating activity. Despite its significance in controlling SR protein function and splicing, little is known about the Clk enzymes. Using novel phosphate mapping and structural techniques combined with cell-based assays, we will investigate how the Clk kinases hyper-phosphorylate SR proteins and modulate splicing.

描述（由申请人提供）：虽然正确选择剪接位点对基因组多样性、适应性生长和发育至关重要，但剪接错误可能对功能产生巨大的有害影响，并且现在被认为是许多人类疾病的潜在原因。事实上，剪接错误与肌肉萎缩症、阿尔茨海默病、帕金森病、精神疾病、共济失调和癌症有关，这使得研究控制剪接位点选择的因素对人类疾病至关重要。剪接发生在剪接体上，剪接体是由几种rna和许多蛋白质组成的大分子复合物。正常基因剪接的关键是正确选择5‘和3’剪接位点