Nuclear hormone receptors: Ancient 9aaTAD and evolutionally gained NCoA activation pathways

[Display omitted] •Two activation pathways in ancient and modern hormone receptors.•Ancient canonical pathway dependent on activation domain 9aaTAD.•Newly gained alternative pathway dependent on incoming NCoA adaptors.•Adjacent H11 domains have an inhibitory effect on 9aaTADs and cause their dormancy. In higher metazoans, the nuclear hormone receptors activate transcription trough their specific adaptors, nuclear hormone receptor adaptors NCoA, which are absent in lower metazoans. The Nine amino acid TransActivation Domain, 9aaTAD, was reported for a large number of the transcription activators that recruit general mediators of transcription. In this study, we demonstrated that the 9aaTAD from NHR-49 receptor of nematode C.elegans activates transcription as a small peptide. We showed that the ancient 9aaTAD domains are conserved in the nuclear hormone receptors including human HNF4, RARa, VDR and PPARg. Also their small 9aaTAD peptides effectively activated transcription in absence of the NCoA adaptors. We also showed that adjacent H11 domains in ancient and modern hormone receptors have an inhibitory effect on their 9aaTAD function.