Nuclear Receptor Superfamily

Nuclear receptors (NRs) are important transcription factors capable of exerting regulation of gene expression in the nucleus in response to various extracellular and intracellular signals. NRs are activated by binding of small hydrophobic compounds, such as steroids, retinoids, and thyroid hormones. The interaction of ligand and receptor triggers a conformational change in the receptor proteins, which enables an interaction with cofactors and specific cis-regulatory DNA sequences called hormone response elements (HREs) to subsequently modify gene expression. NRs are involved in widely diverse physiological functions such as control of development, reproduction, metabolism, cell differentiation, and homeostasis. NRs share a similar modular domain structure, which includes, from N-terminus to C-terminus: 1) domains A and B make up the highly variable (both in length and sequence) amino/N-terminal domain (NTD); 2) the DNA-binding domain (DBD), which consists of two zinc finger DNA-binding motifs; 3) the hinge D-region, often contains the main nuclear localization sequence (NLS); 4) the ligand-binding domain (LBD); 5) some receptors also contain a short, variable carboxy/C-terminal domain (CTD; F domain). Most NRs are regulated endogenously by small lipophilic ligands, but this protein family also contains “orphan” members for which lack identified ligand molecules. NRs are divided into seven subfamilies, Subgroup 0 to Subgroup 6, based on sequence alignment and phylogenetic tree construction. Among them, the Subgroup 1 is large family which is formed by thyroid hormone receptors (TR), retinoic acid receptors (RAR), peroxisome proliferator activated receptors (PPAR), reverse-Erb receptors (REV-ERB, retinoic acid related receptors (ROR), farnesoid X receptors (FXR), liver X receptors (LXR), and vitamin D receptors (VDR).