The importance of intrinsic disorder for protein phosphorylation

Lilia M. Iakoucheva, Predrag Radivojac, Celeste J. Brown, Timothy R. O'Connor, Jason G. Sikes, Zoran Obradovic, A. Keith Dunker

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983 Scopus citations


Reversible protein phosphorylation provides a major regulatory mechanism in eukaryotic cells. Due to the high variability of amino acid residues flanking a relatively limited number of experimentally identified phosphorylation sites, reliable prediction of such sites still remains an important issue. Here we report the development of a new web-based tool for the prediction of protein phosphorylation sites, DISPHOS (DISorder-enhanced PHOSphorylation predictor, We observed that amino acid compositions, sequence complexity, hydrophobicity, charge and other sequence attributes of regions adjacent to phosphorylation sites are very similar to those of intrinsically disordered protein regions. Thus, DISPHOS uses position-specific amino acid frequencies and disorder information to improve the discrimination between phosphorylation and non-phosphorylation sites. Based on the estimates of phosphorylation rates in various protein categories, the outputs of DISPHOS are adjusted in order to reduce the total number of misclassified residues. When tested on an equal number of phosphorylated and non-phosphorylated residues, the accuracy of DISPHOS reaches 76% for serine, 81% for threonine and 83% for tyrosine. The significant enrichment in disorder-promoting residues surrounding phosphorylation sites together with the results obtained by applying DISPHOS to various protein functional classes and proteomes, provide strong support for the hypothesis that protein phosphorylation predominantly occurs within intrinsically disordered protein regions.

Original languageEnglish (US)
Pages (from-to)1037-1049
Number of pages13
JournalNucleic acids research
Issue number3
StatePublished - Jul 14 2004

ASJC Scopus subject areas

  • Genetics

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    Iakoucheva, L. M., Radivojac, P., Brown, C. J., O'Connor, T. R., Sikes, J. G., Obradovic, Z., & Dunker, A. K. (2004). The importance of intrinsic disorder for protein phosphorylation. Nucleic acids research, 32(3), 1037-1049.