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Updated: Jun 29, 2026
Immunopeptidomics: Isolation of Mouse and Human MHC Class I- and II-Associated Peptides for Mass Spectrometry Analysis
Published on: October 15, 2021
Structure of WDR5 bound to mixed lineage leukemia protein-1 peptide
Anamika Patel1, Venkatasubramanian Dharmarajan, Michael S Cosgrove
1Department of Biology, Syracuse University, Syracuse, New York 13244, USA.
Abstract:
The mixed lineage leukemia protein-1 (MLL1) catalyzes histone H3 lysine 4 methylation and is regulated by interaction with WDR5 (WD-repeat protein-5), RbBP5 (retinoblastoma-binding protein-5), and the Ash2L (absent, small, homeotic discs-2-like) oncoprotein. In the accompanying investigation, we describe the identification of a conserved arginine containing motif, called the "Win" or WDR5 interaction motif, that is essential for the assembly and H3K4 dimethylation activity of the MLL1 core complex. Here we present a 1.7-A crystal structure of WDR5 bound to a peptide derived from the MLL1 Win motif. Our results show that Arg-3765 of MLL1 is bound in the same arginine binding pocket on WDR5 that was previously suggested to bind histone H3. Thermodynamic binding experiments show that the MLL1 Win peptide is preferentially recognized by WDR5. These results are consistent with a model in which WDR5 recognizes Arg-3765 of MLL1, which is essential for the assembly and enzymatic activity of the MLL1 core complex.
Insights
Researchers identified a WDR5 interaction motif (Win) in mixed lineage leukemia protein-1 (MLL1). This motif is crucial for MLL1 complex assembly and H3K4 dimethylation activity, revealing a key interaction for epigenetic regulation.
Area of Science:
- Molecular Biology
- Epigenetics
- Structural Biology
Background:
- Mixed lineage leukemia protein-1 (MLL1) is a key epigenetic regulator catalyzing histone H3 lysine 4 methylation.
- MLL1 activity is dependent on its core complex, including WDR5, RbBP5, and Ash2L.
- Understanding MLL1-WDR5 interactions is critical for deciphering epigenetic mechanisms.
Purpose of the Study:
- To identify and characterize the WDR5 interaction motif (Win) within MLL1.
- To elucidate the structural basis of the MLL1-WDR5 interaction.
- To determine the functional significance of the Win motif for MLL1 complex assembly and activity.
Main Methods:
- Identification of a conserved arginine-containing motif (Win) in MLL1.
- X-ray crystallography to determine the structure of WDR5 bound to an MLL1 Win motif peptide.
- Thermodynamic binding experiments to assess binding affinity and specificity.
Main Results:
- A conserved WDR5 interaction motif (Win) in MLL1 was identified and shown to be essential for MLL1 complex assembly and H3K4 dimethylation.
- The crystal structure revealed that MLL1's Arg-3765 binds to the same pocket on WDR5 that binds histone H3.
- Thermodynamic data indicated preferential binding of the MLL1 Win peptide by WDR5.
Conclusions:
- WDR5 directly recognizes the MLL1 Win motif, specifically Arg-3765.
- This interaction is essential for the assembly and enzymatic activity of the MLL1 core complex.
- The findings provide structural and mechanistic insights into MLL1 regulation and its role in epigenetics.
