PMID:26324722

Citation	Shinsky, SA and Cosgrove, MS (2015) Unique Role of the WD-40 Repeat Protein 5 (WDR5) Subunit within the Mixed Lineage Leukemia 3 (MLL3) Histone Methyltransferase Complex. J. Biol. Chem. 290:25819-33
Abstract	The MLL3 (mixed lineage leukemia 3) protein is a member of the human SET1 family of histone H3 lysine 4 methyltransferases and contains the conserved WDR5 interaction (Win) motif and the catalytic suppressor of variegation, enhancer of zeste, trithorax (SET) domain. The human SET1 family includes MLL1-4 and SETd1A/B, which all interact with a conserved subcomplex containing WDR5, RbBP5, Ash2L, and DPY-30 (WRAD) to form the minimal core complex required for full methyltransferase activity. However, recent evidence suggests that the WDR5 subunit may not be utilized in an identical manner within all SET1 family core complexes. Although the roles of WDR5 within the MLL1 core complex have been extensively studied, not much is known about the roles of WDR5 in other SET1 family core complexes. In this investigation, we set out to characterize the roles of the WDR5 subunit in the MLL3 core complex. We found that unlike MLL1, the MLL3 SET domain assembles with the RbBP5/Ash2L heterodimer independently of the Win motif-WDR5 interaction. Furthermore, we observed that WDR5 inhibits the monomethylation activity of the MLL3 core complex, which is dependent on the Win motif. We also found evidence suggesting that the WRAD subcomplex catalyzes weak H3K4 monomethylation within the context of the MLL3 core complex. Furthermore, solution structures of the MLL3 core complex assembled with and without WDR5 by small angle x-ray scattering show similar overall topologies. Together, this work demonstrates a unique role for WDR5 in modulating the enzymatic activity of the MLL3 core complex.
Links	PubMed PMC4646236 Online version:10.1074/jbc.M115.684142
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:KMT2A		GO:0097692: histone H3-K4 monomethylation	ECO:0000314:		P		Figure 1A	complete CACAO 11228
HUMAN:WDR5		GO:0051572: negative regulation of histone H3-K4 methylation	ECO:0000314:		P		"The MLL3 core complex in the presence of WDR5 shows only H3K4 monomethylation activity that is stimulated in comparison with the isolated MLL3 SET domain but is ∼64-fold slower than the monomethylation rate catalyzed by the MLL1 core complex" Fig. 1D, 1F, 6A and Table 1	complete CACAO 11225
HUMAN:WDR5		GO:0051571: positive regulation of histone H3-K4 methylation	ECO:0000314:		P		WDR5 stimulates H3K4 monomethylation and dimethylation in complex MLL1 Figure 1C When the assays were conducted with complexes that omitted the WDR5 subunit, the MLL1 core complex displayed a 64-fold decrease in the rate of H3K4 mono-methylation compared with the holo-MLL1 core complex and nearly abolished detectable levels of H3K4 di-methylation (Fig. 1E and Table 1)	complete CACAO 11227
HUMAN:KMT2C		GO:0097692: histone H3-K4 monomethylation	ECO:0000314:		P		Figure 1B	complete CACAO 11229

References

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