An updated evolutionary study of the nuclear receptor protein family

The nuclear receptor (NR) superfamily is comprised of transcription factors that are ligand‑activated in their majority and play a pivotal role in biological functions that are essential for life, such as metabolism and homeostasis. Following activation, they undertake the regulation of the transcription of their target genes with the help of co‑regulator proteins, rendering them very promising pharmacological targets. In total, 59 NRs have been discovered in several species of the Animalia kingdom, 20 of which are still orphan receptors. The present study aimed to further enlighten the evolutionary scenario that reveals the association between members of the NR superfamily. An updated evolutionary analysis was performed for the NR protein superfamily with the aim of clustering all the NRs, and discovering conserved regions and motifs that play major roles in their signaling pathway; the mechanisms of action were also investigated. The findings of the present study demonstrate a clear separation of the NR family in three majors monophyletic branches, the steroid hormone‑related, the thyroid hormone‑related and the retinoid X receptor‑related clusters, from which, through evolution, may correspond to three ancestral NRs that were differentiated from a common ancestral NR.