Structure, dynamics and function of RNA binding proteins

RNA结合蛋白的结构、动力学和功能

• 批准号: 8918669
• 负责人: Francesca Massi
• 金额: $ 31.26万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918669
• 关键词: Accounting; Affinity; Amino Acids; Apoptosis; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Process; Breast; Cell Proliferation; Cells; Cessation of life; Chimeric Proteins; Chronic; Computer Simulation; Coupled; Data; Discrimination; Disease; Family; Family member; Fluorescence Spectroscopy; Functional disorder; Future; Gene Expression Regulation; Genetic Transcription; Glioma; Goals; Growth Factor; Human; Individual; Inflammation; Laboratories; Lead; Ligands; Link; Malignant Neoplasms; Mammalian Cell; Measures; Mediating; Messenger RNA; Molecular; NMR Spectroscopy; Phenotype; Phosphorylation; Physiologic pulse; Play; Process; Production; Prostate; Protein Binding; Protein Family; Proteins; RNA; RNA Binding; RNA Recognition Motif; RNA-Binding Proteins; Radioactive; Recruitment Activity; Regulation; Resistance; Role; Serine; Site-Directed Mutagenesis; Specificity; Staging; Structure; TIS11 protein; Techniques; Testing; United States; Vascularization; Work; Zinc Fingers; angiogenesis; base; biophysical techniques; cancer type; conformational conversion; cytokine; flexibility; improved; in vivo; innovation; interdisciplinary approach; mRNA Decay; mRNA Transcript Degradation; member; molecular dynamics; novel therapeutic intervention; protein function; research study; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Regulation of gene expression is central to efficient biological function. Two key aspects of this process are the synthesis of mRNA (transcription) and control of its stability. The goal of this proposal is to understand how an important class of proteins, the CCCH zinc finger proteins of the tristetraprolin (TTP) family, recognizes and binds to mRNA to promote its degradation. This process provides an important mechanism for reducing the synthesis of key cytokines and growth factors that regulate inflammation and the initiation and progression of cancer. To understand the function and regulation of TTP in the cell we will use an integrated approach that combines NMR spectroscopy, computer simulation, biochemical and in vivo experiments. Our detailed biophysical and biochemical characterizations of TTP-mRNA interactions will determine the mechanism of TTP-mediated mRNA destabilization that is relevant for cancer and inflammation.

描述(由申请人提供)：基因表达调控是有效生物功能的核心。这一过程的两个关键方面是mRNA的合成(转录)和对其稳定性的控制。这项研究的目的是了解一类重要的蛋白质，即Tristetraprolin(TTP)家族的CCCH锌指蛋白，是如何识别并结合mRNA以促进其降解的。这一过程为减少关键细胞因子和生长因子的合成提供了重要机制，这些因子和生长因子调节炎症和癌症的发生和发展。为了了解TTP在细胞中的功能和调节，我们将使用结合核磁共振光谱、计算机模拟、生化和体内实验的综合方法。我们对TTP-mRNA相互作用的详细生物物理和生化特征将确定TTP介导的与癌症和炎症相关的mRNA失稳的机制。

项目成果

Structural Basis of the Disorder in the Tandem Zinc Finger Domain of the RNA-Binding Protein Tristetraprolin.

• DOI: 10.1021/acs.jctc.6b00150
• 发表时间: 2016-10-11
• 期刊: JOURNAL OF CHEMICAL THEORY AND COMPUTATION
• 影响因子: 5.5
• 作者: Tavella, Davide;Deveau, Laura M.;Whitfield, Troy W.;Massi, Francesca
• 通讯作者: Massi, Francesca

Structural Rearrangement upon Fragmentation of the Stability Core of the ALS-Linked Protein TDP-43.

• DOI: 10.1016/j.bpj.2017.06.049
• 发表时间: 2017-08
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Brittany R. Morgan;J. Zitzewitz;F. Massi

Insight into the allosteric mechanism of Scapharca dimeric hemoglobin.

• DOI: 10.1021/bi500591s
• 发表时间: 2014-11-25
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Laine, Jennifer M.;Amat, Miguel;Morgan, Brittany R.;Royer, William E., Jr.;Massi, Francesca
• 通讯作者: Massi, Francesca