Nerve Growth Factor IB-like Receptor

Nerve growth factor IB like receptor, also called NR4A subfamily, is an evolutionary ancient and highly conserved group of orphan nuclear receptors (NRs) of transcription factors, including Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3). They act as transcription factors that directly modulate gene expression, but can also form trans-repressive complexes with other transcription factors. In contrast to other members of the NR superfamily, NR4A receptors function in ligand-independent manner and are rapidly induced by a pleiotropy of environmental stimuli, including growth factors, inflammatory stimuli, cytokines, peptide hormones, and cellular stress. Structurally, like other nuclear receptors, NR4A receptors are composed of a central two-zinc DNA-binding domain, an N-terminal transactivation domain, and a C-terminal ligand-binding domain (LBD). The three members reveal a high degree of homology in their genomic structure and conservation of their DNA binding domain (degree of conservation > 90%). The LBD lacks a classical hydrophobic binding pocket, explaining ligand-independent action. They recognize the NGFI-B-responsive element (NBRE) motif (AAAAGGTCA) on DNA as monomers and they can bind as homodimers to the palindromic DNA binding motif, NurRE (TGATATTTX6AAATGCCCA) in promoter sequences of its downstream target genes. NR4A receptors function as ligand-independent NR and early-response genes regulating key cellular processes, including inflammation, apoptosis, survival, proliferation, differentiation, DNA repair, and fatty acid metabolism. Moreover, they are involved in the onset and progression of numerous diseases, such as obesity, atherosclerosis, inflammation and cancer.