Published online 11 February 2004
Nucleic Acids Research, 2004, Vol. 32, No. 3 1037-1049
© 2004 Oxford University Press
The importance of intrinsic disorder for protein phosphorylation
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA and 1 Center for Information Science and Technology, Temple University, Philadelphia, PA 19122, USA
*To whom correspondence should be addressed at: Biochemistry and Molecular Biology, 635 Barnhill Drive, MS 4023, Indianapolis, IN 46202-5122, USA. Tel: +1 317 278 9650; Fax: +1 317 274 4686; Email: kedunker{at}iupui.edu
Present addresses:
Lilia M. Iakoucheva, The Rockefeller University, Laboratory of Statistical Genetics, New York, NY 10021, USA
Celeste J. Brown, IBEST, University of Idaho, Moscow, ID 83844-1010, USA
A. Keith Dunker, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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, http://www.ist.temple. edu/DISPHOS). 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.
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