Structural basis for H3K4 trimethylation by yeast Set1/COMPASS

Abstract

Histone methylation on lysine 4 of histone H3 (H3K4) is a hallmark of activity of the transcribed regions on eukaryotic chromatin. H3K4 can be mono-, di- and trimethylated by Set1/COMPASS. In this review, we will discuss recent findings regarding the role of the Y/F switch by the catalytic domain of Set1 in the regulation of H3K4 methylation by Set1/COMPASS.

Figure 1. Homology model of the catalytic domain of Set1

a.) Ribbon representation of the secondary structure of the Set1 catalytic domain illustrating the SET domain (blue) and PostSET motif (magenta). A histone H3 substrate peptide spanning residues 1-6 (orange carbon atoms) and the product S-adenosyl-L-homocysteine (AdoHcy; green carbons) are docked in the active site. The side chains of the four cysteines that coordinate the Zn ion in the PostSET domain are also illustrated. b.) Active site of Set1. Residues comprising the enzyme’s active sites are shown with gray carbon atoms, while the residues mutated in this study are highlighted with magenta carbons. AdoHcy and H3K4 are depicted as in (a). Hydrogen bonds are illustrated by cyan dashed lines.

Figure 2. Model illustrating the Cps40 and 60 function in the regulation of HMTase activity of Set1/COMPASS

Cps40 and Cps60 (depicted in yellow diamond) induces the conformational change of Set1/SET domain such that pulling back Tyr1052 (light purple trapezoid) so that its HMTase active site encompassing the substrate of di-methylated lysine gets to be more open making it easier to accommodate tri-methylated lysine. In the Y1052F mutant Set1, mono- and di-methylation proceed similarly to wild-type. However, F1052 (dark purple) lacking the hydroxyl group (blue small trapezoid) from the phenol ring side chain, allows enough space for methyl transfer to the trimethylated H3 peptide without the aid of Cps40. This model is consistent with our previous observation that the loss of Cps60 and Cps40 results in the loss H3K4 trimethylation (Schinder et al., 2005). Our molecular modeling and experimental results demonstrating complementation of H3K4 trimethylation in a SetY1052F in the absence of Cps40 strongly supports this model. Arg1013 (blue rectangle), whose substitution results in the complete loss of H3K4 methylation, should be involved in holding and/or the arrangement of the cofactor SAM on its own or via an interaction with Y993 (Figure 1b).