PROSITE documentation PDOC00031

Nuclear hormone receptors DNA-binding domain signature and profile

Nuclear hormone receptors are ligand-activated transcription factors that regulate gene expression by interacting with specific DNA sequences upstream of their target genes. In vertebrates, these proteins regulate diverse biological processes such as pattern formation, cellular differentiation and homeostasis [1,2,3,4,5,6].

Classical nuclear hormone receptors contain two conserved regions, the hormone binding domain and a DNA-binding domain (DBD) that is composed of two C4-type zinc fingers. The DBD is responsible for targeting the receptors to their hormone response elements (HRE). It binds as a dimer with each monomer recognizing a six base pair sequence of DNA. The vast majority of targets contain the same 5'-AGGTCA-3' consensus sequence [7]. In some cases a less conserved C-terminal extension of the core DBD confers the DNA selectivity [8].

The two zinc fingers fold to form a single structural domain (see <PDB:1HCQ>) [9,10]. The structure consists of two helices perpendicular to each other. A zinc ion, coordinated by four conserved cysteines, holds the base of a loop at the N terminus of each helix. The helix of each monomer makes sequence specific contacts in the major groove of the DNA.

Proteins known to contain a nuclear hormone receptor DNA-binding domain are listed below:

• Androgen receptor (AR).
• Estrogen receptor (ER).
• Glucocorticoid receptor (GR).
• Mineralocorticoid receptor (MR).
• Progesterone receptor (PR).
• Retinoic acid receptors (RARs and RXRs).
• Thyroid hormone receptors (TR) α and β.
• The avian erythroblastosis virus oncogene v-erbA, derived from a cellular thyroid hormone receptor.
• Vitamin D3 receptor (VDR).
• Insects ecdysone receptor (EcR).
• COUP transcription factor (also known as ear-3), and its Drosophila homolog seven-up (svp).
• Hepatocyte nuclear factor 4 (HNF-4), which binds to DNA sites required for the transcription of the genes for α-1-antitrypsin, apolipoprotein CIII and transthyretin.
• Ad4BP, a protein that binds to the Ad4 site found in the promoter region of steroidogenic P450 genes.
• Apolipoprotein AI regulatory protein-1 (ARP-1), required for the transcription of apolipoprotein AI.
• Peroxisome proliferator activated receptors (PPAR), transcription factors specifically activated by peroxisome proliferators. They control the peroxisomal β-oxidation pathway of fatty acids by activating the gene for acyl-CoA oxidase.
• Drosophila protein knirps (kni), a zygotic gap protein required for abdominal segmentation of the Drosophila embryo.
• Drosophila protein ultraspiracle (usp) (or chorion factor 1), which binds to the promoter region of s15 chorion gene.
• Human estrogen receptor related genes 1 and 2 (err1 and err2).
• Human erbA related gene 2 (ear-2).
• Mammalian NGFI-B (NAK1, nur/77, N10).
• Mammalian NOT/nurR1/RNR-1.
• Drosophila protein embryonic gonad (egon).
• Drosophila knirps-related protein (knrl).
• Drosophila protein tailless (tll).
• Drosophila 20-oh-ecdysone regulated protein E75.
• Insects Hr3.
• Insects Hr38.
• Caenorhabditis elegans cnr-8, cnr-14, and odr-7
• Caenorhabditis elegans hypothetical proteins B0280.8, EO2H1.7 and K06A1.4.

As a signature pattern for this family of proteins, we took the most conserved residues, the first 27, of the DNA-binding domain. We also developed a profile that spans the whole domain.