6 Structure of SET domain protein lysine methyltransferases

Methylation of lysine residues is now understood to constitute a key component of the complex signaling paradigm referred to as the histone code hypothesis. Rapid progress has been made in the structural and functional biology of the enzymes responsible for this modification. TheseSET proteins are based on a common fold that appears unique to this family. The structure of the SET domain is such that peptide substrates bind on one surface, whereas the AdoMet cofactor binds on the opposite side of the domain. Remarkably, the target lysine residue gains access to the cofactor by passing through a channel that runs through the SET domain connecting these two binding surfaces. Different SET enzymes carry out mono-, di-, or tri-methylation of their targets, and these modifications give rise to distinctive biological readouts. Ternary complexes of several SET enzymes reveal how the size and bonding patterns of residues flanking the active site determine the multiplicity of methylation that occurs. Indeed, the methylation multiplicity of some of these enzymes has been engineered by specifically mutating residues close to the active site. The catalytic activity of SET enzymes depends on adjacent domains at theirN- and C-termini. The N-flanking domains seem important for structural stability but the C-flanking domains are necessary for the completion of the active sites of these enzymes. Recent NMR studies have shown that these C-flanking domains are flexible and that their ordering, driven by substrate binding, is an important part of the catalytic cycle of these enzymes.