title: Intrinsic protein disorder in histone lysine methylation.
abstract: Histone lysine methyltransferases (HKMTs), catalyze mono-, di- and trimethylation of lysine residues, resulting in a regulatory pattern that controls gene expression. Their involvement in many different cellular processes and diseases makes HKMTs an intensively studied protein group, but scientific interest so far has been concentrated mostly on their catalytic domains. In this work we set out to analyze the structural heterogeneity of human HKMTs and found that many contain long intrinsically disordered regions (IDRs) that are conserved through vertebrate species. Our predictions show that these IDRs contain several linear motifs and conserved putative binding sites that harbor cancer-related SNPs. Although there are only limited data available in the literature, some of the predicted binding regions overlap with interacting segments identified experimentally. The importance of a disordered binding site is illustrated through the example of the ternary complex between MLL1, menin and LEDGF/p75. Our suggestion is that intrinsic protein disorder plays an as yet unrecognized role in epigenetic regulation, which needs to be further elucidated through structural and functional studies aimed specifically at the disordered regions of HKMTs.
  
  
  
  This article was reviewed by Arne Elofsson and Piotr Zielenkiewicz.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary.|Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Práter utca 50/a, 1083, Budapest, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Lazar
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary.
authors.forename: Eva
authors.initials: E
authors.lastname: Schad
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary.
authors.forename: Beata
authors.initials: B
authors.lastname: Szabo
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Horvath
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Meszaros
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary.|VIB Structural Biology Research Center (SBRC), Pleinlaan 2, 1050, Brussels, Belgium.|Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Tompa
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary. tantos.agnes@ttk.mta.hu.
authors.forename: Agnes
authors.initials: A
authors.lastname: Tantos
mesh_terms: D001665:Binding Sites; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000737:chemistry*; D006801:Humans; D008239:Lysine / Q000737:chemistry*; D008745:Methylation
chemical_list: D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine
keywords: Binding regions; Epigenetics; Histone lysine methyltransferases; Intrinsically disordered protein regions; Linear motifs; MLL proteins; Posttranslational modifications