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.
| Hsu, Wei-Lun; Oldfield, Christopher J; Xue, Bin et al. (2013) Exploring the binding diversity of intrinsically disordered proteins involved in one-to-many binding. Protein Sci 22:258-73 |
| Xue, Bin; Romero, Pedro R; Noutsou, Maria et al. (2013) Stochastic machines as a colocalization mechanism for scaffold protein function. FEBS Lett 587:1587-91 |
| Xue, Bin; Dunker, A Keith; Uversky, Vladimir N (2012) The roles of intrinsic disorder in orchestrating the Wnt-pathway. J Biomol Struct Dyn 29:843-61 |
| Hsu, Wei-Lun; Oldfield, Christopher; Meng, Jingwei et al. (2012) Intrinsic protein disorder and protein-protein interactions. Pac Symp Biocomput :116-27 |
| Johnson, Derrick E; Xue, Bin; Sickmeier, Megan D et al. (2012) High-throughput characterization of intrinsic disorder in proteins from the Protein Structure Initiative. J Struct Biol 180:201-15 |
| Huang, Fei; Oldfield, Christopher; Meng, Jingwei et al. (2012) Subclassifying disordered proteins by the CH-CDF plot method. Pac Symp Biocomput :128-39 |
| Disfani, Fatemeh Miri; Hsu, Wei-Lun; Mizianty, Marcin J et al. (2012) MoRFpred, a computational tool for sequence-based prediction and characterization of short disorder-to-order transitioning binding regions in proteins. Bioinformatics 28:i75-83 |
| Brown, Celeste J; Johnson, Audra K; Dunker, A Keith et al. (2011) Evolution and disorder. Curr Opin Struct Biol 21:441-6 |
| Hu, Yang; Liu, Yunlong; Jung, Jeesun et al. (2011) Changes in predicted protein disorder tendency may contribute to disease risk. BMC Genomics 12 Suppl 5:S2 |
| Hong, Dong-Pyo; Han, Shubo; Fink, Anthony L et al. (2011) Characterization of the non-fibrillar ýý-synuclein oligomers. Protein Pept Lett 18:230-40 |
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