Abstract
The immunophilin FKBP51 forms heterocomplexes with molecular chaperones, protein-kinases, protein-phosphatases, autophagy-related factors, and transcription factors. Like most scaffold proteins, FKBP51 can use a simple tethering mechanism to favor the efficiency of interactions with partner molecules, but it can also exert more complex allosteric controls over client factors, the immunophilin itself being a putative regulation target. One of the simplest strategies for regulating pathways and subcellular localization of proteins is phosphorylation. In this study, it is shown that scaffold immunophilin FKBP51 is resolved by resolutive electrophoresis in various phosphorylated isoforms. This was evidenced by their reactivity with specific anti-phosphoamino acid antibodies and their fade-out by treatment with alkaline phosphatase. Interestingly, stress situations such as exposure to oxidants or in vivo fasting favors FKBP51 translocation from mitochondria to the nucleus. While fasting involves phosphothreonine residues, oxidative stress involves tyrosine residues. Molecular modeling predicts the existence of potential targets located at the FK1 domain of the immunophilin. Thus, oxidative stress favors FKBP51 dephosphorylation and protein degradation by the proteasome, whereas FK506 binding protects the persistence of the post-translational modification in tyrosine, leading to FKBP51 stability under oxidative conditions. Therefore, FKBP51 is revealed as a phosphoprotein that undergoes differential phosphorylations according to the stimulus.