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: 6950310
• 负责人: ALAN KEITH DUNKER
• 金额: $ 32.44万
• 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: 2003-09-30 至 2007-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950310
• 关键词: RNA splicing; biological signal transduction; data collection methodology /evaluation; genome; intermolecular interaction; mathematics; messenger RNA; molecular biology information system; molecular shape; nuclear magnetic resonance spectroscopy; phosphorylation; protein binding; protein protein interaction; protein sequence; protein structure function; thermodynamics

DESCRIPTION (provided by applicant): The overall goal is to understand the relationships between intrinsic disorder and protein function. Lack of data and lack of annotation have limited our previous research, so the first aims will be to enlarge and exhaustively annotate our ordered and disordered protein databases. Using the annotated data, we propose next to compare different bioinformatics and datamining strategies to find the optimal approach for the order/disorder problem. Even with the current incomplete data and annotation, we were able to discover that more than 100 disordered protein regions carry out at least 28 distinct functions that fall into four broad categories: molecular recognition, protein modification, entropic chains, and molecular assembly /disassembly. Several experiments are proposed herein to further understanding of disorder/function relationships for the first three of these categories: 1. Molecular recognition: the hypothesis to be tested is that proteins involved in signal transduction and celt regulation commonly use intrinsic disorder for recognizing their binding targets; 2. Protein modification: the hypothesis to be tested is that chemical modification primarily involves residues that are located within intrinsically disordered regions possibly due to the requirement for disorder-to-order transitions as the targets fold onto to their modifying enzymes (special emphasis will be placed on phosphorylation, but g!ycosylation, acetylation, ubiquitination, and other modifications, will be considered as time permits); and 3. Entropic chains:: the hypothesis to be tested is that alternative splicing in mRNAs occurs mostly in regions that code for disordered protein because this location circumvents difficulties associated with the successful folding of different length, but otherwise identical proteins. The proposed research has important implications for human disease, especially various cancers, for as we have recently shown, many and probably the large majority of cancer-associated proteins have significant regions of intrinsic disorder.

描述（由申请人提供）： 总体目标是了解内在紊乱与蛋白质功能之间的关系。缺乏数据和注释限制了我们之前的研究，因此首要目标是扩大和详尽注释我们的有序和无序蛋白质数据库。使用带注释的数据，我们接下来建议比较不同的生物信息学和数据挖掘策略，以找到有序/无序问题的最佳方法。即使目前的数据和注释不完整，我们仍然能够发现超过 100 个无序蛋白质区域执行至少 28 种不同的功能，分为四大类：分子识别、蛋白质修饰、熵链和分子组装/拆卸。本文提出了几个实验，以进一步理解这些类别中前三类的紊乱/功能关系： 1.分子识别：要测试的假设是参与信号转导和细胞调节的蛋白质通常使用内在紊乱来识别其结合靶点； 2. 蛋白质修饰：要测试的假设是，化学修饰主要涉及位于本质上无序区域内的残基，可能是由于当靶标折叠到其修饰酶上时需要无序到有序的转变（特别强调磷酸化，但如果时间允许，将考虑糖基化、乙酰化、泛素化和其他修饰）； 3. 熵链：要测试的假设是，mRNA 中的选择性剪接主要发生在编码无序蛋白质的区域，因为该位置规避了与成功折叠不同长度但其他方面相同的蛋白质相关的困难。拟议的研究对人类疾病，特别是各种癌症具有重要意义，因为正如我们最近所表明的，许多（可能是绝大多数）癌症相关蛋白具有显着的内在紊乱区域。