title: Solution NMR structure and histone binding of the PHD domain of human MLL5.
abstract: Mixed Lineage Leukemia 5 (MLL5) is a histone methyltransferase that plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. In addition to its catalytic domain, MLL5 contains a PHD finger domain, a protein module that is often involved in binding to the N-terminus of histone H3. Here we report the NMR solution structure of the MLL5 PHD domain showing a variant of the canonical PHD fold that combines conserved H3 binding features from several classes of other PHD domains (including an aromatic cage) along with a novel C-terminal α-helix, not previously seen. We further demonstrate that the PHD domain binds with similar affinity to histone H3 tail peptides di- and tri-methylated at lysine 4 (H3K4me2 and H3K4me3), the former being the putative product of the MLL5 catalytic reaction. This work establishes the PHD domain of MLL5 as a bone fide 'reader' domain of H3K4 methyl marks suggesting that it may guide the spreading or further methylation of this site on chromatin.
authors.affiliation: Northeast Structural Genomics Consortium and Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lemak
authors.forename: Adelinda
authors.initials: A
authors.lastname: Yee
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Damian
authors.initials: D
authors.lastname: Yap
authors.forename: Hong
authors.initials: H
authors.lastname: Zeng
authors.forename: Ludmila
authors.initials: L
authors.lastname: Dombrovski
authors.forename: Scott
authors.initials: S
authors.lastname: Houliston
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D012996:Solutions
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C460660:KMT2E protein, human; D012996:Solutions