Structure and Conformational Dynamics of a COMPASS Histone H3K4 Methyltransferase Complex

The methylation of histone 3 lysine 4 (H3K4) is carried out by an evolutionarily conserved family of methyltransferases referred to as complex of proteins associated with Set1 (COMPASS). The activity of the catalytic SET domain (su(var)3-9, enhancer-of-zeste, and trithorax) is endowed through forming a complex with a set of core proteins that are widely shared from yeast to humans. We obtained cryo-electron microscopy (cryo-EM) maps of the yeast Set1/COMPASS core complex at overall 4.0- to 4.4-Å resolution, providing insights into its structural organization and conformational dynamics. The Cps50 C-terminal tail weaves within the complex to provide a central scaffold for assembly. The SET domain, snugly positioned at the junction of the Y-shaped complex, is extensively contacted by Cps60 (Bre2), Cps50 (Swd1), and Cps30 (Swd3). The mobile SET-I motif of the SET domain is engaged by Cps30, explaining its key role in COMPASS catalytic activity toward higher H3K4 methylation states. [Display omitted] •Cryo-EM structure of a fully active H3K4 methyltransferase COMPASS complex•The assembly of COMPASS is orchestrated by Cps50•The catalytic SET protein is structurally coordinated by Cps60, Cps50, and Cps30•The methylation product specificity of COMPASS is modulated by Cps30 The cryo-EM structure of a fully functional COMPASS complex reveals the intricate structural coordination of the methyltransferase subunit by its partner proteins.