Bioinformatics linkage of protein disorder and function

蛋白质紊乱与功能的生物信息学联系

• 批准号: 7620178
• 负责人: ALAN KEITH DUNKER
• 金额: $ 44.15万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620178
• 关键词: Active Sites; Alternative Splicing; Amino Acids; Back; Binding; Biochemistry; Bioinformatics; Cardiovascular Diseases; Catalysis; Cellular Structures; Classification; Code; Collection; Complex; DNA-Protein Interaction; Data; Development; Dimensions; Disease; Enzymes; Erinaceidae; Eukaryota; Eukaryotic Cell; Event; Goals; Grant; Heterogeneous Nuclear RNA; Indium; Investigation; Knowledge; Laboratories; Lead; Learning; Malignant Neoplasms; Membrane Proteins; Molecular Chaperones; Multiple Partners; Organism; Pathway interactions; Play; Protein Region; Proteins; RNA; RNA-Protein Interaction; Regulation; Research; Ribosomal Proteins; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Spliceosomes; Structure; Testing; Textbooks; Tissues; Work; base; cell type; computerized data processing; concept; data mining; drug discovery; feeding; human disease; mRNA Precursor; molecular recognition; notch protein; novel; protein function; protein protein interaction; small molecule; three dimensional structure; transcription factor

The overall goal of this project is to better understand the relationship between intrinsic disorder (ID) and protein function. Much has been learned since the the first submission of the proposal that became the grant for the first 4 years of this project. This is due to the activity of our research team supported by the previous grant and also due to the significantly intensified research of other laboratories on the intrinsically disordered proteins (IDPs). However, many important questions remained unanswered as of yet. Therefore, this proposal is focused on five major problems: 1) Association between protein ID and alternative splicing (AS) of pre-mRNA (AS is believed to represent a crucial event responsible for the functional profiling of many protein in eukaryotes, including proteins in such important pathways as Notch, Wnt, Hedgehog, PAR, and TGF ); 2) Characterization of disorder-to-order transitions induced in IDPs by interaction with their binding partners (with the major focus on the development of predictors of molecular recognition features (MoRFs) from sequence); 3) Understanding sequence-function relationships for ID regions associated with specific functions (with the primary focus on the discovery of novel functions associated with intrinsic disorder and finding functions specific for MoRFs, ELMs, Fmotifs, SMART, or Pfam motifs); 4) Characterization of the relationships between ID and single nucleotide polymorphisms (SNPs) that occur in coding regions (to check a hypothesis that a large fraction of disease related SNPs are located in ordered regions, since a substitution of a buried amino-acid is more likely to disrupt the structure stability of a protein and alter its function); and 5) Characterization of protein-RNA interactions (to test the hypothesis that the protein-RNA interactions frequently involve disorder-to-order transitions of the protein components). For each of these aims, a set of specific proteins will be collected or significantly enlarged with the major emphasis on the exhaustive and thorough annotation of disordered and ordered regions. Using these annotated data, we propose next to compare different bioinformatics and datamining strategies to find the optimal approaches for the disorder/order problem. The proposed research has important implications for human diseases, since many proteins involved in numerous human diseases (including cancer and cardiovascular diseases) have significant ID regions and their structures and functions of are modulated by AS and SNPs.

该项目的总体目标是更好地理解内在障碍（ID）和 蛋白质功能。自首次提交该提案以来，我们已经学到了很多东西，该提案成为了 该项目前 4 年的补助金。这是由于我们的研究团队的活动得到了 之前的资助，也归功于其他实验室对本质的研究的显着加强 无序蛋白质（IDP）。然而，许多重要问题尚未得到解答。 因此，该提案主要关注五个主要问题：1）蛋白质ID与蛋白质之间的关联 前体 mRNA 的选择性剪接 (AS)（AS 被认为代表了导致 真核生物中许多蛋白质的功能分析，包括以下重要途径中的蛋白质 Notch、Wnt、Hedgehog、PAR 和 TGF）； 2) 诱导的无序到有序转变的表征 国内流离失所者通过与其结合伙伴的互动（主要关注发展预测因子） 来自序列的分子识别特征（MoRF）； 3）理解序列函数 与特定功能相关的 ID 区域的关系（主要关注于发现 与内在紊乱相关的新功能，并寻找 MoRF、ELM、Fmotif 特有的功能， SMART 或 Pfam 图案）； 4) ID与单核苷酸关系的表征 编码区中发生的多态性 (SNP)（以检验很大一部分疾病的假设） 相关的 SNP 位于有序区域，因为埋藏氨基酸的替换更有可能 破坏蛋白质的结构稳定性并改变其功能）； 5) 蛋白质-RNA 的表征 相互作用（检验蛋白质-RNA相互作用经常涉及从无序到有序的假设 蛋白质成分的转变）。对于每个目标，将收集一组特定蛋白质或 显着扩大，主要强调对无序的详尽和彻底的注释 和有序区域。使用这些带注释的数据，我们接下来建议比较不同的生物信息学和 数据挖掘策略来寻找无序/有序问题的最佳方法。拟议的 研究对人类疾病具有重要意义，因为许多蛋白质涉及许多人类疾病 疾病（包括癌症和心血管疾病）具有显着的 ID 区域及其结构 的功能受 AS 和 SNP 调节。