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.
Highlights
Histone H3 lysine 4 methylation catalyzed by the mixed lineage leukemia protein-1 (MLL1) is important for the regulation of hox genes in hematopoiesis and development [1,2,3]
In the accompanying investigation [22], we describe the identification of a WDR5 interaction motif, or “Win” motif, which is located in the N-SET region of MLL1
We demonstrate that the MLL1 Win motif is highly conserved among metazoan SET1 family members and is recognized by WDR5 in a mechanism that is crucial for the assembly and enzymatic activity of the MLL1 core complex in vitro
Summary
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. Our functional results suggest that WDR5 preferentially recognizes the conserved Arg-3765 within the MLL1 Win motif using the same arginine binding site as suggested previously for histone H3. To test this hypothesis, we determined the crystal structure of WDR5 bound to a peptide derived from the MLL1 Win motif. These results suggest that the previously observed histone H3-WDR5 interaction may not be relevant for the enzymatic activity of the MLL1 core complex
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