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Recently, a second type of interaction has been suggested, mediated by short segments termed <jats:italic>linear motifs<\/jats:italic>, which are related to recognition elements of intrinsically disordered regions. Here, we propose a third kind of protein\u2013protein recognition mechanism, mediated by disordered regions longer than 20\u201330 residues. Bioinformatics predictions and well\u2010characterized examples, such as the kinase\u2010inhibitory domain of Cdk inhibitors and the Wiskott\u2013Aldrich syndrome protein (WASP)\u2010homology domain 2 of actin\u2010binding proteins, show that these disordered regions conform to the definition of domains rather than motifs, <jats:italic>i.e<\/jats:italic>., 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.<\/jats:p>","DOI":"10.1002\/bies.200800151","type":"journal-article","created":{"date-parts":[[2009,3,3]],"date-time":"2009-03-03T14:32:15Z","timestamp":1236090735000},"page":"328-335","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":233,"title":["Close encounters of the third kind: disordered domains and the interactions of proteins"],"prefix":"10.1002","volume":"31","author":[{"given":"Peter","family":"Tompa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Fuxreiter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Oldfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Simon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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