Database: PROSITE(DOC)
Entry: PDOC50280
LinkDB: PDOC50280
Original site: PDOC50280 
{PS50280; SET}
{PS50867; PRE_SET}
{PS50868; POST_SET}
* Pre-SET, post-SET and SET domain profiles *

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 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. [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
 - 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
 - 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.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: May 2013 / Profile revised.

[ 1] Jenuwein T., Laible G., Dorn R., Reuter G.
     "SET domain proteins modulate chromatin domains in eu- and
     Cell. Mol. Life Sci. 54:80-93(1998).
[ 2] Rea S., Eisenhaber F., O'Carroll D., Strahl B.D., Sun Z.W., Schmid M.,
     Opravil S., Mechtler K., Ponting C.P., Allis C.D., Jenuwein T.
     "Regulation of chromatin structure by site-specific histone H3
     Nature 406:593-599(2000).
     PubMed=10949293; DOI=10.1038/35020506
[ 3] Zhang X., Tamaru H., Khan S.I., Horton J.R., Keefe L.J., Selker E.U.,
     Cheng X.
     "Structure of the Neurospora SET domain protein DIM-5, a histone H3
     lysine methyltransferase."
     Cell 111:117-127(2002).
[ 4] Wilson J.R., Jing C., Walker P.A., Martin S.R., Howell S.A.,
     Blackburn G.M., Gamblin S.J., Xiao B.
     "Crystal structure and functional analysis of the histone
     methyltransferase SET7/9."
     Cell 111:105-115(2002).
[ 5] Trievel R.C., Beach B.M., Dirk L.M., Houtz R.L., Hurley J.H.
     "Structure and catalytic mechanism of a SET domain protein
     Cell 111:91-103(2002).
[ 6] Huang S., Shao G., Liu L.
     "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. 273:15933-15939(1998).
[ 7] Schubert H.L., Blumenthal R.M., Cheng X.
     "Many paths to methyltransfer: a chronicle of convergence."
     Trends. Biochem. Sci. 28:329-335(2003).
[ 8] Yeates T.O.
     "Structures of SET domain proteins: protein lysine methyltransferases
     make their mark."
     Cell 111:5-7(2002).
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