Regulatory Pathways of SR Protein Kinases

SR蛋白激酶的调控途径

基本信息

批准号：
8503353
负责人：
JOSEPH ADAMS
金额：
$ 31万
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：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8503353
关键词：
Active Sites Affect Alternative Splicing Alzheimer&apos s Disease Arginine Ataxia Binding Biological Biological Process C-terminal Catalysis Cell Nucleus Cell physiology Cells Complex Cytoplasm Data Defect Dipeptides Disease Docking Elements Enzymes Family Funding Gene Expression Genes Genetic Materials Health Human Investigation Karyopherins Lobe Macromolecular Complexes Malignant Neoplasms Messenger RNA Metabolic Diseases Modeling Modification Molecular Molecular Chaperones Muscular Dystrophies Myopathy N Domain N-terminal Neurodegenerative Disorders Nuclear Nuclear Matrix-Associated Proteins Nucleotides Organism Parkinsonian Disorders Pathology Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Process Processed Genes Protein Dephosphorylation Protein Family Protein Fragment Protein Kinase Protein-Serine-Threonine Kinases Proteins Proteome RNA RNA Splicing Regulation Regulatory Pathway Role SAFB gene Serine Signal Transduction Site Spliced Genes Spliceosome Assembly Pathway Spliceosomes Structure Substrate Specificity Translations Work acrosome stabilizing factor bioprocess feeding human disease inorganic phosphate insight mRNA Precursor novel protein activation protein function protein protein interaction prototype public health relevance release factor scaffold

项目摘要

DESCRIPTION (provided by applicant): Splicing is a co-transcriptional process whereby a single gene can be converted into multiple unique mRNA fragments for enhanced protein diversity. While splicing is integral for normal cellular function in complex organisms, mistakes i splice-selection can be extremely deleterious. In fact, splicing errors are associated with numerous human diseases including muscular dystrophy, Alzheimer's disease, parkinsonism, metabolic disorders, ataxias and cancers. Splicing occurs at the spliceosome, a macromolecular complex that includes both RNA and proteins. In the latter group, SR proteins are essential splicing factors that control where and how the spliceosome assembles on precursor mRNA. SR proteins contain C-terminal domains rich in arginine-serine repeats whose polyphosphorylation controls splice-site selection. The SRPK family of protein kinases phosphorylates these RS domains directing SR proteins into the nucleus for splicing activity. While SRPKs are normally localized to the cytoplasm for this function, they can enter the nucleus under certain conditions further affecting SR protein phosphorylation levels and alternative gene splicing. Although phosphorylation is critical for splice-site choice, very little is known about how residue-specific phosphorylation of SR proteins controls alternative gene splicing. Clearly, knowing how the SRPKs are regulated in the cell and how they recognize and phosphorylate SR proteins is essential for an understanding of gene splicing and disease pathologies related to mis-splicing. We showed that SRPKs and phosphatases work in opposite directions concentrating phosphates toward the C-terminal end of RS domains. We will now explore how this unique phosphate distribution termed "phosphate biasing" affects SR protein function. We recently showed that the catalytic activity of SRPK1 is dependent on a nucleotide release factor composed of sequence elements from a large insert domain and an N-terminal extension. We propose that this conserved release factor is a hub for SRPK regulation in the cell. We will demonstrate how phosphorylation and protein-protein interactions modulate this factor and regulate SR protein phosphorylation levels and gene splicing.

描述（由申请人提供）：剪接是一个共转录过程，可以将单个基因转换为多个独特的mRNA片段以增强蛋白质多样性。尽管剪接是复杂生物中正常细胞功能不可或缺的一部分，但我剪接选择的错误可能是极其有害的。实际上，剪接错误与许多人类疾病有关，包括肌肉营养不良，阿尔茨海默氏病，帕金森病，代谢性疾病，共济失调和癌症。剪接发生在剪接体，这是一种包括RNA和蛋白质的大分子复合物。在后一组中，SR蛋白是控制剪接体在前体mRNA上的何处以及如何组装的基本剪接因子。 SR蛋白包含富含精氨酸丝氨酸重复的C末端结构域，其多磷酸化控制剪接位点的选择。蛋白激酶的SRPK家族磷酸化这些RS结构域，将SR蛋白引导到细胞核中以进行剪接活性。尽管SRPK通常位于该功能的细胞质中，但它们可以在某些条件下进入核进一步影响SR蛋白磷酸化水平和替代基因剪接。尽管磷酸化对于剪接站点的选择至关重要，但对残基特异性的方式知之甚少 SR蛋白的磷酸化控制替代基因剪接。显然，知道如何在细胞中调节SRPK，以及它们如何识别和磷酸化SR蛋白对于理解与错误分解有关的基因剪接和疾病病理至关重要。我们表明，SRPK和磷酸酶在相反的方向上工作，将磷酸盐集中在RS结构域的C末端。现在，我们将探讨这种称为“磷酸盐偏置”的独特磷酸盐分布如何影响SR蛋白功能。我们最近表明，SRPK1的催化活性取决于由大型插入域和N末端扩展的序列元件组成的核苷酸释放因子。我们建议这种保守的释放因子是细胞中SRPK调节的枢纽。我们将展示磷酸化和蛋白质蛋白相互作用如何调节该因子并调节SR蛋白磷酸化水平和基因剪接。