Abstract
Mixed Lineage Leukemia 5 (MLL5) is a histone methyltransferase that plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. In addition to its catalytic domain, MLL5 contains a PHD finger domain, a protein module that is often involved in binding to the N-terminus of histone H3. Here we report the NMR solution structure of the MLL5 PHD domain showing a variant of the canonical PHD fold that combines conserved H3 binding features from several classes of other PHD domains (including an aromatic cage) along with a novel C-terminal α-helix, not previously seen. We further demonstrate that the PHD domain binds with similar affinity to histone H3 tail peptides di- and tri-methylated at lysine 4 (H3K4me2 and H3K4me3), the former being the putative product of the MLL5 catalytic reaction. This work establishes the PHD domain of MLL5 as a bone fide ‘reader’ domain of H3K4 methyl marks suggesting that it may guide the spreading or further methylation of this site on chromatin.
Highlights
Post translational modifications of histones are a key epigenetic mechanism used to regulate gene transcription, chromatin condensation, DNA damage sensing and repair
Mixed Lineage Leukemia 5 (MLL5) and observed very similar structural features compared to other PHD fingers
It was reported that in MLL5 knockdown cells, H3K4 methylation at the cell cycle regulated element is reduced [16], and H3K4 trimethylation levels are reduced at E2F1 target promoters [25]
Summary
Post translational modifications of histones are a key epigenetic mechanism used to regulate gene transcription, chromatin condensation, DNA damage sensing and repair. Key among these modifications are protein lysine acetylation and methylation. These modifications are ‘‘written’’ or ‘‘erased’’ by chromatinassociated proteins that have the specific catalytic activities. These modifications are in turn recognized by ‘‘reader’’ domain(s) of proteins that are recruited to the chromatin. Proteins with PHD fingers are mostly nuclear [10] and often involved in chromatin remodelling. PHD fingers studied so far recognize several different histone trimethyllysine marks [11,12] as well as unmodified histone H3 N-terminus [13,14], and possibly acetyllysine [15]
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