PROSITE documentation PDOC00924

NF-kappa-B/Rel/dorsal domain signature and profile

Various studies (reviewed in [1,2,3,4,5]) have allowed the characterization of a family of eukaryotic transcription factors with basic impact on oncogenesis, embryonic development and differentiation including immune response and acute phase reaction. Most of these transcription factors bind as dimers to the consensus DNA sequence motif 5'-GGGRNNYYCC-3' termed kappa-B according the first described factor-binding sequence motif located in the immunoglobulin kappa light chain enhancer region.

Proteins of this family appear to be regulated, at least in part, by subcellular localization whereby the inactive cytoplasmic forms become active transcriptional control proteins by translocation to the nucleus. Members of the Rel family share a highly conserved 300 amino acids domain termed Rel homology domain (RHD) which is located towards the amino terminus. The unique C-terminal is thought to be involved in gene activation and cytoplasmic anchoring functions.

Proteins known to contain a RHD domain are listed below:

• Both subunits of vertebrate nuclear factor NF-kappa-B. The active NF-kappa- B is a heterodimer of an about 50 Kd DNA-binding subunit (p50 or p49, p52) and the transcription factor p65.
• Mammalian transcription factor RelB, which stimulates promoter activity in the presence of the 50 Kd subunit of NF-kappa-B.
• Vertebrate proto-oncogene c-rel, a protein that may play a role in differentiation and lymphopoiesis.
• Avian reticuloendotheliosis virus p58 v-rel, a transforming protein which induces acute leucemia in juvenile birds.
• Drosophila embryonic polarity dorsal protein. The concentration of this morphogenetic protein in the nucleus during the blastoderm stage determines the lateral or ventral identity of a cell. It directly controls the expression of zygotically active genes crucial for development along this axis.
• Drosophila dorsal-related immunity factor (gene Dif) which mediates an immune response in the larvae.
• Mammalian nuclear factor of activated T cells (NFAT); a family of transcription factors that play a role in the inducible expression of cytokine genes in T cells.

For several proteins it has been demonstrated ([1] and references therein) that the Rel homology domain includes:

 (1) a  DNA-binding domain, which binds to the consensus  DNA  sequence  motif
     5'-GGGRNNYYCC-3' (except  for  dorsal, which recognizes the related motif
     5'-GRGAAAANCC-3');
 (2) a  dimerization  domain,  which  is located in the C-terminal part of the
     RHD;
 (3) a PKA phosphorylation site (see <PDOC00004>) (except in RelB);
 (4) a nuclear localization signal (NLS),  which consists of a stretch of four
     or five basic residues.

As a signature for this family we selected a region that is located at the N-terminal of the RHD. This region includes a conserved cysteine that seems to be essential for DNA-binding in p50 [6]. We also developed a profile that spans completly the RHD.