The paired domain is a ~126 amino acid DNA-binding domain, which is found in eukaryotic transcription regulatory proteins involved in embryogenesis. The domain was originally described as the 'paired box' in the Drosophila protein paired (prd) [1,2]. The paired DNA-binding domain is generally located in the N-terminal part. An octapeptide [3] and/or a homeodomain (see <PDOC00027>) can occur C-terminal to the paired DNA-binding domain, as well as a Pro-Ser-Thr-rich C-terminus. Paired DNA-binding domain proteins can function as transcription repressors or activators. The paired DNA-binding domain contains three subdomains, which show functional differences in DNA-binding.

The crystal structures of prd and Pax proteins show that the DNA-bound paired domain is bipartite, consisting of an N-terminal subdomain (PAI or NTD) and a C-terminal subdomain (RED or CTD), connected by a linker (see <PDB:1K78>). PAI and RED each form a three-helical fold, with the most C-terminal helices comprising a helix-turn-helix (HTH) motif that binds the DNA major groove. In addition, the PAI subdomain encompasses an N-terminal β-turn and β-hairpin, also named 'wing', participating in DNA-binding. The linker can bind into the DNA minor groove. Different Pax proteins and their alternatively spliced isoforms use different (sub)domains for DNA-binding to mediate the specificity of sequence recognition [4,5].

Some proteins known to contain a paired DNA-binding domain:

• Drosophila paired (prd), a segmentation pair-rule class protein.
• Drosophila gooseberry proximal (gsb-p) and gooseberry distal (gsb-d), segmentation polarity class proteins.
• Drosophila Pox-meso and Pox-neuro proteins. The Pax proteins:
• Mammalian protein Pax1, which may play a role in the formation of segmented structures in the embryo. In mouse, mutations in Pax1 produce the undulated phenotype, characterized by vertebral malformations along the entire rostro-caudal axis.
• Mammalian protein Pax2, a probable transcription factor that may have a role in kidney cell differentiation.
• Mammalian protein Pax3. Pax3 is expressed during early neurogenesis. In Man, defects in Pax3 are the cause of Waardenburg's syndrome (WS), an autosomal dominant combination of deafness and pigmentary disturbance.
• Mammalian protein Pax5, also known as B-cell specific transcription factor (BSAP). Pax5 is involved in the regulation of the CD19 gene. It plays an important role in B-cell differentiation as well as neural development and spermatogenesis.
• Mammalian protein Pax6 (oculorhombin). Pax6 is a transcription factor with important functions in eye and nasal development. In Man, defects in Pax6 are the cause of aniridia type II (AN2), an autosomal dominant disorder characterized by complete or partial absence of the iris.
• Mammalian protein Pax8, required in thyroid development.
• Mammalian protein Pax9. In man, defects in Pax9 cause oligodontia.
• Zebrafish proteins Pax[Zf-a] and Pax[Zf-b].

We use the region spanning positions 34 to 50 of the paired DNA-binding domain as a signature pattern. This conserved region spans the DNA-binding HTH located in the N-terminal subdomain. We also developed a profile that covers the entire paired DNA-binding domain, including the PAI and RED subdomains and which allows a more sensitive detection.