1. Structural and Biochemical Insights into MLL1 Core Complex Assembly
- Author
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Jean-François Couture, Sylvain Lanouette, Adam F. Groulx, Pamela Zhang, Joseph S. Brunzelle, Véronique Tremblay, and Vanja Avdic
- Subjects
Methyltransferase ,Stereochemistry ,Recombinant Fusion Proteins ,Amino Acid Motifs ,Molecular Sequence Data ,Sequence alignment ,Plasma protein binding ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Protein structure ,Structural Biology ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Protein Structure, Quaternary ,Ternary complex ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Methylation ,Histone-Lysine N-Methyltransferase ,3. Good health ,Protein Structure, Tertiary ,DNA-Binding Proteins ,Histone ,030220 oncology & carcinogenesis ,biology.protein ,Protein Multimerization ,Sequence Alignment ,Myeloid-Lymphoid Leukemia Protein ,Protein Binding - Abstract
SummaryHistone 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.
- Published
- 2011
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