Structural Insight into Recognition of Methylated Histone H3K4 by Set3

- Set3 PHD finger binds H3K4me3 and H3K4me2 with comparable affinities.
- Composition of the methyllysine-binding pocket confers selectivity.
- The Set3-like aromatic cage is not sufficient to induce binding of Set4 to H3.

The plant homeodomain (PHD) finger of Set3 binds methylated lysine 4 of histone H3 in vitro and in vivo; however, precise selectivity of this domain has not been fully characterized. Here, we explore the determinants of methyllysine recognition by the PHD fingers of Set3 and its orthologs. We use X-ray crystallographic and spectroscopic approaches to show that the Set3 PHD finger binds di- and trimethylated states of H3K4 with comparable affinities and employs similar molecular mechanisms to form complexes with either mark. Composition of the methyllysine-binding pocket plays an essential role in determining the selectivity of the PHD fingers. The finding that the histone-binding activity is not conserved in the PHD finger of Set4 suggests different functions for the Set3 and Set4 paralogs.

Graphical Abstract92