Structural and Biochemical Insights into MLL1 Core Complex Assembly

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...

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Bibliographic Details
Published in:Structure (London) 2011-01, Vol.19 (1), p.101-108
Main Authors: Avdic, Vanja, Zhang, Pamela, Lanouette, Sylvain, Groulx, Adam, Tremblay, Véronique, Brunzelle, Joseph, Couture, Jean-François
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Amino Acid Sequence
Assembly
Binding
Biochemistry
Bridges (structures)
Histone-Lysine N-Methyltransferase - chemistry
Histones
Humans
Molecular Sequence Data
Myeloid-Lymphoid Leukemia Protein - chemistry
Nuclear Proteins - chemistry
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
Protein Structure, Quaternary
Protein Structure, Tertiary
Recombinant Fusion Proteins - chemistry
Residues
Segments
Sequence Alignment
Stimulation
Vanadium
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Summary: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. ► A 50-residue segment of RbBP5 bridges the Ash2L C-terminal domain to WDR5 ► The structure demonstrates how WDR5 binds RbBP5 and MLL1 ► Binding MLL1 and RbBP5 is mediated by two independent peptide-binding clefts ► Two hydrophobic residues are linchpin in conferring binding of RbBP5 to WDR5
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2010.09.022