Regulation of FKBP51 and FKBP52 functions by post-translational modifications

DANERI-BECERRA C, ZGAJNAR N, LOTUFO C, RAMOS A, PIWIEN PILIPUK G, GALIGNIANA MD

BIOCHEMICAL SOCIETY TRANSACTIONS

PORTLAND PRESS LTD

Lugar: Londres; Año: 2019 vol. 47 p. 1815 - 1831

0300-5127

Immunophilins are a family of proteins whose signature domain is the peptidylprolyl-isomerase domain. High molecular weight immunophilins have additional tetratricopeptide-repeat sequences through which they bind Hsp90 and regulate the biological functions of several client-proteins. The subfamily of immunophilins capable to bind the immunosuppressive macrolide FK506 is called FKBP (FK506-Binding Protein). FKBP51 (51-kDa) was first described in cytosolic complexes with unliganded steroid-receptors. Surprisingly, we evidenced that FKBP51 is a mitochondrial factor that undergoes nuclear-mitochondrial shuttling upon the onset of stress and shows anti-apoptotic action. The subcellular redistribution of FKBP51 depends on the activation of the transcription factor HSF1. Moreover, we have also demonstrated that FKBP51 is a phosphoprotein. Interestingly, cytosolic, nuclear and mitochondrial pools of FKBP51 exhibit different levels of phosphorylation, the mitochondrial fraction being the most phosphorylated fraction. Phospho-amino acid analysis revealed that Thr is the most phosphorylated residue in non-neuronal cells, followed to a lesser extent by Tyr, whereas no phospho-Ser was detected. Interestingly, the phosphorylation pattern of FKBP51 is different in neuronal cells since Tyr and Ser (in that order) are the most phosphorylated residues. These findings were also supported by the analysis of specific phospho-amino acid residues in the crystal structure of FKBP51. It will be discussed how the subcellular localization and the biological properties of FKBP51 are differentially modified by endocrine stimulation and/or during the cell differentiation process