InterPro domain: IPR001214

The SET domain is a 130 to 140 amino acid, evolutionary well conserved sequence motif that was initially characterised 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 [ 3 ]. 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 [ 3 , 4 ].

The structure of the SET domain and the two adjacent regions pre-SET and post-SET have been solved [ 5 , 6 , 7 ]. The SET structure is all beta, 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 [ 8 , 9 , 9 ]. 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 [ 9 , 9 ].

1. SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell. Mol. Life Sci. 54, 80-93
2. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593-9
3. Many paths to methyltransfer: a chronicle of convergence. Trends Biochem. Sci. 28, 329-35
4. Structures of SET domain proteins: protein lysine methyltransferases make their mark. Cell 111, 5-7
5. Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Cell 111, 117-27
6. Crystal structure and functional analysis of the histone methyltransferase SET7/9. Cell 111, 105-15
7. Structure and catalytic mechanism of a SET domain protein methyltransferase. Cell 111, 91-103
8. The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin-mediated gene expression. J. Biol. Chem. 273, 15933-9