title: Structural and biochemical insights into MLL1 core complex assembly.
abstract: Histone H3 Lys-4 methylation is predominantly catalyzed by a family of methyltransferases whose enzymatic activity depends on their interaction with a three-subunit complex composed of WDR5, RbBP5, and Ash2L. Here, we report that a segment of 50 residues of RbBP5 bridges the Ash2L C-terminal domain to WDR5. The crystal structure of WDR5 in ternary complex with RbBP5 and MLL1 reveals that both proteins binds peptide-binding clefts located on opposite sides of WDR5's β-propeller domain. RbBP5 engages in several hydrogen bonds and van der Waals contacts within a V-shaped cleft formed by the junction of two blades on WDR5. Mutational analyses of both the WDR5 V-shaped cleft and RbBP5 residues reveal that the interactions between RbBP5 and WDR5 are important for the stimulation of MLL1 methyltransferase activity. Overall, this study provides the structural basis underlying the formation of the WDR5-RbBP5 subcomplex and further highlight the crucial role of WDR5 in scaffolding the MLL1 core complex.
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Vanja
authors.initials: V
authors.lastname: Avdic
authors.forename: Pamela
authors.initials: P
authors.lastname: Zhang
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lanouette
authors.forename: Adam
authors.initials: A
authors.lastname: Groulx
authors.forename: Véronique
authors.initials: V
authors.lastname: Tremblay
authors.forename: Joseph
authors.initials: J
authors.lastname: Brunzelle
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Couture
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry*; D009687:Nuclear Proteins / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry*; D016415:Sequence Alignment
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; C470552:RBBP5 protein, human; D011993:Recombinant Fusion Proteins; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase