Bioinformatics linkage of protein disorder and function

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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.