The SET domain is an 130- to 140-amino acid, evolutionary well conserved sequence motif that was initially characterized in the Drosophila proteins Su(var)3-9, Enhancer-of-zeste and Trithorax. In addition to these chromosomal proteins modulating gene activities and/or chromatin structure, the SET domain is found in proteins of diverse functions ranging from yeast to mammals, but also including some bacteria and viruses [1,2].

The SET domains of mammalian SUV39H1 and 2 and fission yeast clr4 have been shown to be necessary for the methylation of lysine-9 in the histone H3 N-terminus [2]. However, this histone methyltransferase (HMTase) activity is probably restricted to a subset of SET domain proteins as it requires the combination of the SET domain with the adjacent cysteine-rich regions, one located N-terminally (pre-SET) and the other posterior to the SET domain (post-SET). Post- and pre- SET regions seem then to play a crucial role when it comes to substrate recognition and enzymatic activity [7,8].

Structure of the SET domain and the two adjacent regions pre-SET and post-SET have been solved (see <PDB:1ML9>) [3,4,5]. The SET structure is all β, but consists only in sets of few short strands composing no more than a couple of small sheets. Consequently the SET structure is mostly defined by turns and loops. An unusual feature is that the SET core is made up of two discontinual segments of the primary sequence forming an approximate L shape. [6,7,8]. Two of the most conserved motifs in the SET domain are constituted by (1) a stretch at the C-terminal containing a strictly conserved tyrosine residue and (2) a preceding loop inside which the C-terminal segment passes forming a knot-like structure, but not quite a true knot. These two regions have been proven to be essential for SAM binding and catalysis, particularly the invariant tyrosine where in all likelihood catalysis takes place [7,8].

The pre-SET domain forms a triangular zinc cluster where nine cysteines coordinate three zinc atoms. Each zinc ion is coordinated by two unique cysteines and the remaining three cysteines are shared by two zinc atoms serving as a bridge to complete the tetrahedral coordination of the metal. A similar metal cluster is found in methallothioneins.

The PR domain, first noted as the PRDI-BF1-RIZ1 homologous region, is found in a sub-class of zinc finger containing proteins that appear to function as negative regulators of tumorigenesis. Its significant sequence identity with the SET domain has led to suggest that the PR domain is a derivative of SET domain [6].

Some proteins currently known to include a SET or PR domain are listed below:

• Arabidopsis thaliana CURLY LEAF (CLF) protein. It is homologous to the Drosophila E(z) protein and is necessary for stable repression of a floral homeotic gene.
• Drosophila Enhancer-of-zeste (E(z)), which belongs to the polycomb group of genes needed to maintain the segment specific repression of homeotic genes.
• Drosophila Suppressor of variegation 3-9 (Su(var)3-9), heterochromatic protein implied in position effect variegation.
• Drosophila Trithorax (trx). Founding member of the trithorax group of genes needed to maintain the segment specific activation of homeotic genes.
• Fission yeast cryptic loci regulator 4 (clr4), the homolog of Drosophila Su(var)3-9. It is essential for silencing of centromeres and the mating- type loci.
• Mammalian Hrx protein. In human, this homologue of Trx implicated in the onset of translocation-induced leukaemia.
• Mammalian PRDI-BF1/Blimp-1, a PR domain containing protein, which acts as a transcriptional repressor of the c-myc oncogene.
• Mammalian retinoblastoma-interacting zinc-finger protein 1 (RIZ1). RIZ1 contains a N-terminal PR domain.
• Mammalian SUV39H1 and SUV39H2. Homologs of Drosophila Su(var)3-9 and fission yeast clr4.
• Some plant methyltransferase. They contain an insertion of about 100 amino acids in the middle of the SET domain and do not comprise a SET-domain- associated cysteine-rich region or the C-terminal tail with its three cysteines.
• Yeast SET1. Important for mating-type switching and telomeric silencing.

We have developed a profile that detects both the SET domain and the closely related PR domain. We also developed two other profiles, one specific for the pre-SET domain and the other for the post-SET domain. Each profile covers the whole domain for which it was developed.