Evolution of Nuclear Retinoic Acid Receptor Alpha (RARα) Phosphorylation Sites. Serine Gain Provides Fine-Tuned Regulation

Samarut, E., Amal, I., Markov, G.V., Stote, R., Dejaegere, A., Laudet, V., and Rochette-Egly, C.
Mol. Biol. Evol.   28(7): 2125-37 (Journal)
Registered Authors
Laudet, Vincent, Samarut, Eric
nuclear retinoic acid receptor, phosphorylation, evolution
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • COS Cells
  • Catalytic Domain
  • Chlorocebus aethiops
  • Cyclin H/chemistry
  • Cyclin H/metabolism
  • Evolution, Molecular*
  • Humans
  • Immunoblotting
  • Mice
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Phosphorylation
  • Phylogeny
  • Proline
  • Receptors, Retinoic Acid/chemistry*
  • Receptors, Retinoic Acid/genetics*
  • Receptors, Retinoic Acid/metabolism
  • Sequence Alignment
  • Serine/genetics*
  • Zebrafish
21297158 Full text @ Mol. Biol. Evol.
The human nuclear retinoic acid (RA) receptor alpha (hRARα) is a ligand-dependent transcriptional regulator, which is controlled by a phosphorylation cascade. The cascade starts with the RA-induced phosphorylation of a serine residue located in the Ligand Binding Domain, S(LBD), allowing the recruitment of the cdk7/cyclinH/MAT1 subcomplex of TFIIH through the docking of cyclin H. It ends by the subsequent phosphorylation by cdk7 of an other serine located in the N-terminal domain, S(NTD). Here we show that this cascade relies on an increase in the flexibility of the domain involved in cyclin H binding, subsequently to the phosphorylation of S(LBD). Owing to the functional importance of RARα in several vertebrate species, we investigated whether the phosphorylation cascade was conserved in zebrafish (Danio rerio), which expresses two RARα genes, RARα-A and RARα-B. We found that in zebrafish RARαs, S(LBD) is absent, while S(NTD) is conserved and phosphorylated. Therefore we analyzed the pattern of conservation of the phosphorylation sites and traced back their evolution. We found that S(LBD) is most often absent outside mammalian RARα and appears late during vertebrate evolution. In contrast, S(NTD) is conserved, indicating that the phosphorylation of this functional site has been under ancient high selection constraint. This suggests that, during evolution, different regulatory circuits control RARα activity.
Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes