Functional Anthology of Intrinsic Disorder. 3. Ligands, Post-Translational Modifications, and Diseases Associated with Intrinsically Disordered Proteins

Abstract

Currently, the understanding of the relationships between function, amino acid sequence and protein structure continues to represent one of the major challenges of the modern protein science. As much as 50% of eukaryotic proteins are likely to contain functionally important long disordered regions. Many proteins are wholly disordered but still possess numerous biologically important functions. However, the number of experimentally confirmed disordered proteins with known biological functions is substantially smaller than their actual number in nature. Therefore, there is a crucial need for novel bioinformatics approaches that allow projection of the current knowledge from a few experimentally verified examples to much larger groups of known and potential proteins. The elaboration of a bioinformatics tool for the analysis of functional diversity of intrinsically disordered proteins and application of this data mining tool to >200,000 proteins from Swiss-Prot database, each annotated with at least one of the 875 functional keywords was described in the first paper of this series (Xie H., Vucetic S., Iakoucheva L.M., Oldfield C.J., Dunker A.K., Obradovic Z., Uversky V.N. (2006) Functional anthology of intrinsic disorder. I. Biological processes and functions of proteins with long disordered regions. J. Proteome Res.). Using this tool, we have found that out of the 711 Swiss-Prot functional keywords associated with at least 20 proteins, 262 were strongly positively correlated with long intrinsically disordered regions, and 302 were strongly negatively correlated. Illustrative examples of functional disorder or order were found for the vast majority of keywords showing strongest positive or negative correlation with intrinsic disorder, respectively. Some 80 Swiss-Prot keywords associated with disorder-and order-driven biological processes and protein functions were described in the first paper (Xie H., Vucetic S., Iakoucheva L.M., Oldfield C.J., Dunker A.K., Obradovic Z., Uversky V.N. NIH Public Access

Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins

“…Curiously, there is a significant overlap between the sets of modifiable and disorder-promoting residues (with the noticeable exception of Cys and Tyr), whereas the majority of non-modifiable residues (except for Pro) are order-promoting. In agreement with these general observations, phosphorylation (18,25,26), acetylation, acylation, protease digestion, methylation, ubiquitination, and some other PTMs were shown to preferentially occur in IDPRs (18,25,27,28). Therefore, IDPRs serve as carriers of PTMs, with disorder being especially important for regions undergoing multiple PTM events (29).…”

Ubiquitin-independent p53 proteasomal degradation

“…A second proposed mechanism is by formation of protein-protein complexes (Figure 2 option A). 27 Flexibility of structure, in general, has been shown to be associated with binding diversity, 32 and sites of enzyme-catalyzed posttranslational modifications, 33 specifically phosphorylation. 34 There are many proteins that interact with p53.…”

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

“…[26][27][28][29][30][31][32][33] Many of these disorder-utilizing biological functions depend ultimately on disorderbased PPIs. Thus, understanding the structural basis of PPIs involving IDPs is important for a wide variety of biological functions, not just as the mechanistic basis for hub protein function.…”