Bioinformatics linkage of protein disorder and function

描述(由申请人提供)： 总体目标是了解内在紊乱和蛋白质功能之间的关系。有序和无序蛋白质的数据库为这项工作提供了起点。缺乏完整的注释限制了以前的研究，因此第一个目标将是详尽地注释当前的有序和无序蛋白质数据库。即使有不完整的注释，也已经从100多个无序蛋白质中鉴定出28个功能。这些功能分为四类：分子识别、蛋白质修饰、熵链和分子组装与拆解。生物信息学和数据挖掘方法将被用来扩展我们对内在蛋白质无序在这四大功能中的前三个功能中所扮演的角色的知识。1.分子识别：需要检验的假设是，参与信号转导和调控的蛋白质在识别其结合靶标时通常使用固有的障碍。2.蛋白质修饰：需要检验的假设是，化学修饰主要涉及位于内在无序区域的残基，这可能是由于与修饰酶结合时需要进行无序到有序的转变。将特别强调研究磷酸化，但糖基化、乙酰化、泛素化和其他修饰将被认为是时间允许的。3.熵链：需要检验的假设是，mRNAs中的选择性剪接主要发生在编码无序蛋白质的区域，这可能是因为在无序区域定位选择性剪接位点避开了在结构蛋白中定位选择性剪接位点的相关问题。这项拟议的研究对癌症研究具有重要意义，因为正如将显示的那样，许多癌症相关蛋白具有假定的内在紊乱的大范围区域。

DESCRIPTION (provided by applicant): The overall goal is to understand the relationships between intrinsic disorder and protein function. Databases of ordered and disordered proteins provided the starting point for this work. Lack of acomplete annotation limited the previous research, so the first goal will be to exhaustively annotate the current databases of ordered and disordered protein. Even with the incomplete annotation, 28 functions from more than 100 disordered proteins have been identified. These functions fall into four categories: molecular recognition, protein modification, entropic chains, and molecular assembly and disassembly. Bioinformatics and datamining methods will be used to extend ourknowledge of the roles that intrinsic protein disorder plays in the first three of these four broad set of functions. 1. Molecular recognition: the hypothesis to be tested is that proteins involved in signal transduction and regulation commonly use intrinsic disorder in 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 upon binding to the modifying enzyme. Special emphasis will be placed on studying phosphorylation, but glycosylation, acetylation, ubiquitination, and other modifications,will be considered as time permits. 3. Entropic chains: the hypothesis to be tested is that alternative splicing in mRNAs occurs mostly in regions that code for disordered protein possibly because locating alternative splice sites in disordered regions circumvents the problems associated with locating alternative splice sites within structured protein. The proposed research has important implications for cancer research for, as will be shown, many cancer-associated proteins have large regions of putative intrinsic disorder.