PROSITE documentation PDOC00035

POU-specific (POUs) domain signatures and profile and POUs atypical domain profile

The POU (pronounced 'pow') domain [1,2,3,4,5,6,7] is a highly charged 155-162-amino acid region of sequence similarity which has been identified in the three mammalian transcription factors Pit-1, Oct-1, and Oct-2 and in the product of the nematode gene unc-86. The POU domain is a bipartite DNA binding protein module that binds selectively to the DNA octamer motif ATGCAAAT and a subset of derivatives. It consists of two subdomains, a C-terminal homeodomain (POUh) (see <PDOC00027>) and an N-terminal 75- to 82-residue POU-specific (POUs) region separated by a short non-conserved linker. The POU-specific region or 'box' can be subdivided further into two highly conserved regions, A and B, separated by a less highly conserved segment. The POUs domain is always found in association with a POUh domain, and both are required for high affinity and sequence-specific DNA binding.

The POUs domain consists of four α helices packed to enclose an extensive hydrophobic core (see <PDB:1POU>). The POUs domain contains an unusual HTH structure, which differs from the canonical HTH motif in the length of the first α helix and the turn. The region of hypervariability located between subdomains A and B lies within the sequence corresponding to the C-terminal end of helix 2 and the linker between helices 2 and 3. In the model of the POUs-DNA complex, the C-terminus of helix 2 and the turn of the HTH motif project away from the DNA such that sequence variability in this region can be accomodated without adversely affecting DNA binding [8].

Some proteins currently known to contain a POUs domain are listed below:

• Oct-1 (or OTF-1, NF-A1) (gene POU2F1), a transcription factor for small nuclear RNA and histone H2B genes.
• Oct-2 (or OTF-2, NF-A2) (gene POU2F2), a transcription factor that specifically binds to the immunoglobulin promoters octamer motif and activates these genes.
• Oct-3 (or Oct-4, NF-A3) (gene POU5F1), a transcription factor that also binds to the octamer motif.
• Oct-6 (or OTF-6, SCIP) (gene POU3F1), an octamer-binding transcription factor thought to be involved in early embryogenesis and neurogenesis.
• Oct-7 (or N-Oct 3, OTF-7, Brn-2) (gene POU3F2), a nervous-system specific octamer-binding transcription factor.
• Oct-11 (or OTF-11) (gene POU2F3), an octamer-binding transcription factor.
• Pit-1 (or GHF-1) (gene POU1F1), a transcription factor that activates growth hormone and prolactin genes.
• Brn-1 (or OTF-8) (gene POU3F3).
• Brn-3A (or RDC-1) (gene POU4F1), a probable transcription factor that may play a role in neuronal tissue differentiation.
• Brn-3B (gene POU4F2), a probable transcription factor that may play a role in determining or maintaining the identities of a small subset of visual system neurons.
• Brn-3C (gene POU4F3).
• Brn-4 (or OTF-9) (gene POU3F4), a probable transcription factor which exerts its primary action widely during early neural development and in a very limited set of neurons in the mature brain.
• Mpou (or Brn-5, Emb) (gene POU6F1), a transcription factor that binds preferentially to a variant of the octamer motif.
• Skn, that activates cytokeratin 10 (k10) gene expression.
• Sprm-1, a transcription factor that binds preferentially to the octamer motif and that may exert a regulatory function in meiotic events that are required for terminal differentiation of male germ cell.
• Unc-86, a Caenorhabditis elegans transcription factor involved in cell lineage and differentiation.
• Cf1-a, a Drosophila neuron-specific transcription factor necessary for the expression of the dopa decarboxylase gene (dcc).
• I-POU, a Drosophila protein that forms a stable heterodimeric complex with Cf1-a and inhibits its action.
• Drosophila protein nubbin/twain (PDM-1 or DPou-19).
• Drosophila protein didymous (PDM-2 or DPou-28) that may play multiple roles during development.
• Bombyx mori silk gland factor 3 (SGF-3).
• Xenopus proteins Pou1, Pou2, and Pou3.
• Zebrafish proteins Pou1, Pou2, Pou[C], ZP-12, ZP-23, ZP-47 and ZP-50.
• Caenorhabditis elegans protein ceh-6.
• Caenorhabditis elegans protein ceh-18.

HNF1α (MODY3 gene product, the most commonly mutated MODY protein) and HNF1β (hepatocyte nuclear factor 1β; also known as vHNF1 or TCF2) (MODY5 gene product) are atypical members of the POU transcription factors. Their atypical POUs domains have at least one additional α-helix at the N-terminus, and the second helix and adjacent loop of their POUh domains are much longer, creating a more extensive interface between the POUs and POUh domains (see <PDB:2H8R>). This extended interface fixes the relative orientations of the two domains and provides rigidity for DNA recognition as opposed to the flexibility seen in another POU transcription factor, Pit-1 [9,10].

We have derived two signature patterns for the 'POU' domain. The first one spans positions 15 to 27 of the domain, the second positions 42 to 55. We have also developed a profile which covers the entire POUs domain and another that covers the entire atypical POUs domain.