Close encounters of the third kind: Disordered domains and the interactions of proteins

Peter Tompa, Monika Fuxreiter, Christopher J. Oldfield, Istvan Simon, A. Keith Dunker, Vladimir N. Uversky

Research output: Contribution to journalArticle

181 Citations (Scopus)


Protein-protein interactions are thought to be mediated by domains, which are autonomous folding units of proteins. Recently, a second type of interaction has been suggested, mediated by short segments termed linear motifs, which are related to recognition elements of intrinsically disordered regions. Here, we propose a third kind of protein-protein recognition mechanism, mediated by disordered regions longer than 20-30 residues. Bioinformatics predictions and well-characterized examples, such as the kinase-inhibitory domain of Cdk inhibitors and the Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 of actin-binding proteins, show that these disordered regions conform to the definition of domains rather than motifs, i.e., they represent functional, evolutionary, and structural units. Their functions are distinct from those of short motifs and ordered domains, and establish a third kind of interaction principle. With these points, we argue that these long disordered regions should be recognized as a distinct class of biologically functional protein domains.

Original languageEnglish
Pages (from-to)328-335
Number of pages8
Issue number3
Publication statusPublished - Apr 27 2009


  • Disorder in pfam
  • Disordered domain
  • Intrinsically disordered
  • Intrinsically unstructured
  • Pfam domain
  • Unstructured domain

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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