The peptidyl-prolyl isomerase Pin1 regulates phospho-Ser77 retinoic acid receptor alpha stability.

Peptidyl-prolyl isomerases (PPIase) facilitate the cis-trans interconversion of the peptidyl-prolyl bond and in such way affect protein folding. Pin1 is a PPIase, which specifically recognizes phosphorylated S/T-P bonds. The transcription factor TFIIH mediates phosphorylation of the retinoic acid receptor alpha (RARalpha) at position Ser77. In the presence of retinoic acid ...
ligand (RA), the Ser77 non-phosphorylated receptor is suggested to undergo degradation through the proteasome pathway. Here we provide evidence that Pin1 is able to selectively destabilize RARalpha in a ligand independent-manner. We show that this is caused by RARalpha ubiquitination, which in turn is phosphorylation dependent. The single mutation Ser77>A completely abolishes RARalpha degradation whereas the mutation Ser77>E rescues this effect. In addition, we correlate RARalpha stability to Ser77 phosphorylation required for the ligand independent transcriptional activity on fgf8 promoter. Finally, we show that the ligand-independent Ser77 phosphorylation requires the genuine ligand-binding domain.
Mesh Terms:
Amino Acid Substitution, Animals, Binding Sites, CHO Cells, Cricetinae, Cricetulus, Enzyme Activation, Enzyme Stability, Gene Expression Regulation, Enzymologic, Homeostasis, Mutagenesis, Site-Directed, Peptidylprolyl Isomerase, Phosphorylation, Protein Binding, Receptors, Retinoic Acid, Recombinant Proteins, Serine, Structure-Activity Relationship
Biochem. Biophys. Res. Commun.
Date: Mar. 04, 2005
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