SETdomain

The SET domain is a conserved protein domain named after the first three proteins in which it was identified: Su(var)3-9, Enhancer of Zeste, and Trithorax. It constitutes the catalytic core of many histone lysine methyltransferases (KMTs), enzymes that add methyl groups to lysine residues on histone tails. The domain is typically about 130 amino acids long and is often flanked by pre-SET regions rich in cysteines and by post-SET sequences that also coordinate zinc ions, contributing to the domain's structural integrity.

Within the SET domain, a series of conserved motifs coordinate the binding of the methyl donor S-adenosyl-L-methionine (SAM) and the lysine substrate. Depending on the enzyme, SET-domain proteins can catalyze mono-, di-, or tri-methylation of specific lysine residues, most commonly on histone H3. For example, H3K9 methylation is mediated by SUV39 family members, H3K27 by EZH2 in PRC2, and H3K4 by KMT2/SET1 family members. Many SET-domain proteins function as components of larger chromatin-modifying complexes that direct substrate specificity and genomic targeting.

SET-domain proteins are found across eukaryotes, ranging from yeast to humans, and comprise large gene families with diverse domain architectures. Variation includes different pre-SET and post-SET extensions and additional protein interaction motifs, enabling regulation by cellular signals and developmental cues. The precise pattern of histone methylation established by SET-domain enzymes influences chromatin state and transcriptional programs.

Alterations in SET-domain proteins are associated with developmental abnormalities and cancers, underscoring their role in epigenetic regulation. Research on SET-domain enzymes informs understanding of chromatin dynamics, gene regulation, and epigenetic therapies.