Paired domain (Paired_dom)
Type: Domain

The paired domain is an approximately 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) . The paired domain is generally located in the N-terminal part. An octapeptide and/or a homeodomain can occur C-terminal to the paired domain, as well as a Pro-Ser-Thr-rich C terminus.

Paired domain proteins can function as transcription repressors or activators. The paired 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. 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 .

Some proteins known to contain a paired 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, characterised 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 humans, defects in Pax3 are the cause of Waardenburg's syndrome (WS), an autosomal dominant combination of deafness and pigmentary disturbance.

Mammalian protein Pax4 pays an important role in the differentiation and development of pancreatic islet beta cells. It binds to a common element in the glucagon, insulin and somatostatin promoters. In humans, it has been related to the rare, familial, clinically and genetically heterogeneous form of diabetes MODY (maturity-onset diabetes of the young).

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 characterised by complete or partial absence of the iris.

Mammalian protein Pax7 is involved in the regulation of muscle stem cells proliferation, playing a role in myogenesis and muscle regeneration.

Mammalian protein Pax8, required in thyroid development.

Mammalian protein Pax9, required for normal development of thymus, parathyroid glands, ultimobranchial bodies, teeth, skeletal elements of skull and larynx as well as distal limbs. In man, defects in Pax9 cause oligodontia.

Zebrafish protein Paired box protein Pax-2a, involved in the development of the midbrain/hindbrain boundary organizer and specification of neuronal cell fates.

Xenopus laevis protein Paired box protein Pax-3-A, which promotes both hatching gland and neural crest cell fates, two of the cell populations that arise from the neural plate border.