Related Experiment Video
Updated: Jun 29, 2026
Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket
Ji-Joon Song1, Robert E Kingston
1Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Abstract:
WDR5 is a component of the mixed lineage leukemia (MLL) complex, which methylates lysine 4 of histone H3, and was identified as a methylated Lys-4 histone H3-binding protein. Here, we present a crystal structure of WDR5 bound to an MLL peptide. Surprisingly, we find that WDR5 utilizes the same pocket shown to bind histone H3 for this MLL interaction. Furthermore, the WDR5-MLL interaction is disrupted preferentially by mono- and di-methylated Lys-4 histone H3 over unmodified and tri-methylated Lys-4 histone H3. These data implicate a delicate interplay between the effector, WDR5, the catalytic subunit, MLL, and the substrate, histone H3, of the MLL complex. We suggest that the activity of the MLL complex might be regulated through this interplay.
Insights
The WDR5 protein binds the MLL complex using the same site as histone H3. Methylated histone H3 preferentially disrupts this WDR5-MLL interaction, suggesting a regulatory mechanism for the MLL complex.
Area of Science:
- Biochemistry
- Molecular Biology
- Epigenetics
Background:
- The mixed lineage leukemia (MLL) complex is crucial for gene regulation through histone methylation.
- WDR5 is a key component of the MLL complex, involved in binding methylated histone H3.
- Understanding the interactions within the MLL complex is vital for deciphering epigenetic regulation.
Purpose of the Study:
- To elucidate the structural basis of the interaction between WDR5 and the MLL complex.
- To investigate how histone H3 methylation affects the WDR5-MLL interaction.
- To explore the regulatory implications of these interactions on MLL complex activity.
Main Methods:
- X-ray crystallography to determine the structure of WDR5 bound to an MLL peptide.
- Biochemical assays to assess the effect of histone H3 methylation states on WDR5-MLL binding.
Main Results:
- The crystal structure reveals that WDR5 binds the MLL peptide using the identical pocket that binds histone H3.
- Mono- and di-methylated Lys-4 histone H3 preferentially disrupt the WDR5-MLL interaction compared to unmodified or tri-methylated forms.
- These findings highlight a competitive binding mechanism involving WDR5, MLL, and histone H3.
Conclusions:
- WDR5 employs a shared binding site for both histone H3 and the MLL complex.
- Histone H3 methylation status acts as a modulator of the WDR5-MLL interaction.
- This interplay suggests a novel regulatory mechanism controlling the catalytic activity of the MLL complex.
