Structural and biochemical insights into MLL1 core complex assembly

Vanja Avdic, Pamela Zhang, Sylvain Lanouette, Adam Groulx, Véronique Tremblay, Joseph Brunzelle, Jean Franois Couture*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)101-108
Number of pages8
Issue number1
StatePublished - Jan 12 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology


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