La protéine chaperonne Hsp90 dans l'environnement des microtubules (impact de l'acétylation de l'a-tubuline sur sa signalisation et recherche des protéines partenaires/clientes spécifiques de chaque isoforme)

Dans ce projet, nous avons montré que l acétylation de l alpha-tubuline, sous sa forme polymérisée en microtubules, est une modification posttraductionnelle jouant un rôle important dans le recrutement microtubulaire d Hsp90 et sur la régulation de l activité de certaines de ses protéines clientes comme l oncoprotéine Akt/PKB, le suppresseur de tumeur p53 et l enzyme endothéliale eNOS. D autre part, nous avons ident i f ié 78 protéines par tenaires/clientes d Hsp90 dans l environnement des microtubules dont 2 sont potentiellement spécifiques d Hsp90 alpha et 25 d Hsp90 beta.In this work, we have shown that acetylation of alpha-tubulin, when polymerized into microtubules, is a post-translational modification that plays an important role in the recruitment of Hsp90 to the microtubule lattice and also in regulating the activity of some of its client proteins such as the oncoprotein Akt/PKB, the tumor suppressor p53 and the endothelial enzyme eNOS. In addition, we have identified 78 partner/client proteins of Hsp90 in the microtubule environment. Two of them seem to specifically associate with Hsp90 alpha and 25 with Hsp90 beta.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

A decrease in Fkbp52 alters autophagosome maturation and A152T-tau clearance in vivo

The failure of the autophagy-lysosomal pathway to clear the pathogenic forms of Tau exacerbates the pathogenesis of tauopathies. We have previously shown that the immunophilin FKBP52 interacts both physically and functionally with Tau, and that a decrease in FKBP52 protein levels is associated with Tau deposition in affected human brains. We have also shown that FKBP52 is physiologically present within the lysosomal system in healthy human neurons and that a decrease in FKBP52 expression alters perinuclear lysosomal positioning and Tau clearance during Tau-induced proteotoxic stress in vitro. In this study, we generate a zebrafish fkbp4 loss of function mutant and show that axonal retrograde trafficking of Lamp1 vesicles is altered in this mutant. Moreover, using our transgenic HuC::mCherry-EGFP-LC3 line, we demonstrate that the autophagic flux is impaired in fkbp4 mutant embryos, suggesting a role for Fkbp52 in the maturation of autophagic vesicles. Alterations in both axonal transport and autophagic flux are more evident in heterozygous rather than homozygous fkbp4 mutants. Finally, taking advantage of the previously described A152T-Tau transgenic fish, we show that the clearance of pathogenic A152T-Tau mutant proteins is slower in fkbp4+/− mutants in comparison to fkbp4+/+ larvae. Altogether, these results indicate that Fkbp52 is required for the normal trafficking and maturation of lysosomes and autophagic vacuoles along axons, and that its decrease is sufficient to hinder the clearance of pathogenic Tau in vivo

FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story

International audienceThe FK506-binding protein 52 (FKBP52) belongs to a large family of ubiquitously expressed and highly conserved proteins (FKBPs) that share an FKBP domain and possess Peptidyl-Prolyl Isomerase (PPIase) activity. PPIase activity catalyzes the isomerization of Peptidyl-Prolyl bonds and therefore influences target protein folding and function. FKBP52 is particularly abundant in the nervous system and is partially associated with the microtubule network in different cell types suggesting its implication in microtubule function. Various studies have focused on FKBP52, highlighting its importance in several neuronal microtubule-dependent signaling pathways and its possible implication in neurodegenerative diseases such as tauopathies (i.e., Alzheimer disease) and alpha-synucleinopathies (i.e., Parkinson disease). This review summarizes our current understanding of FKBP52 actions in the microtubule environment, its implication in neuronal signaling and function, its interactions with other members of the FKBPs family and its involvement in neurodegenerative disease

The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior

The KAES methodology for efficient evaluation of dependability-related properties is proposed. KAES targets systems representable by Stochastic Petri Nets-based models, composed by a large number of submodels where interconnections are managed through synchronization at action level. The core of KAES is a new numerical solution of the underlying CTMC process, based on powerful mathematical techniques, including Kronecker algebra, Tensor Trains and Exponential Sums. Specifically, advancing on existing literature, KAES addresses efficient evaluation of the Mean-Time-To-Absorption in CTMC with absorbing states, exploiting the basic idea to further pursue the symbolic representation of the elements involved in the evaluation process, so to better cope with the problem of state explosion. As a result, computation efficiency is improved, especially when the submodels are loosely interconnected and have small number of states. An instrumental case study is adopted, to show the feasibility of KAES, in particular from memory consumption point of view

The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior.

International audienc

A β-Turn Motif in the Steroid Hormone Receptor’s Ligand-Binding Domains Interacts with the Peptidyl-prolyl Isomerase (PPIase) Catalytic Site of the Immunophilin FKBP52

International audienceThe immunophilin FKBP52 interacts with nuclear steroid hormone receptors. Studying the crystal structure of human estrogen receptor alpha (hER alpha) and using nuclear magnetic resonance, we show here that the short V(364)PGF(367) sequence, which is located within its ligand-binding domain and adopts a type II beta-turn conformation in the protein, binds the peptidyl-prolyl isomerase (PPIase or rotamase) FK1 domain of FKBP52. Interestingly, this turn motif displays strong similarities with the FKBP52 FK1 domain-binding moiety of macrolide immunomodulators such as rapamycin and GPI-1046, an immunophilin ligand with neuroprotective characteristics. An increase in the hydrophobicity of the residue preceding the proline and cyclization of the VPGF peptide strengthen its recognition by the FK1 domain of FKBP52. Replacement of the Pro residue with a dimethylproline also enhances this interaction. Our study not only contributes to a better understanding of how the interaction between the FK1 domain of FKBP52 and steroid hormone receptors most likely works but also opens new avenues for the synthesis of FKBP52 FK1 peptide ligands appropriate for the control of hormone-dependent physiological mechanisms or of the functioning of the Tau protein. Indeed, it has been shown that FKBP52 is involved in the intraneuronal dynamics of the Tau protein

A β‑Turn Motif in the Steroid Hormone Receptor’s Ligand-Binding Domains Interacts with the Peptidyl-prolyl Isomerase (PPIase) Catalytic Site of the Immunophilin FKBP52

The immunophilin FKBP52 interacts with nuclear steroid hormone receptors. Studying the crystal structure of human estrogen receptor α (hERα) and using nuclear magnetic resonance, we show here that the short V³⁶⁴PGF³⁶⁷ sequence, which is located within its ligand-binding domain and adopts a type II β-turn conformation in the protein, binds the peptidyl-prolyl isomerase (PPIase or rotamase) FK1 domain of FKBP52. Interestingly, this turn motif displays strong similarities with the FKBP52 FK1 domain-binding moiety of macrolide immunomodulators such as rapamycin and GPI-1046, an immunophilin ligand with neuroprotective characteristics. An increase in the hydrophobicity of the residue preceding the proline and cyclization of the VPGF peptide strengthen its recognition by the FK1 domain of FKBP52. Replacement of the Pro residue with a dimethylproline also enhances this interaction. Our study not only contributes to a better understanding of how the interaction between the FK1 domain of FKBP52 and steroid hormone receptors most likely works but also opens new avenues for the synthesis of FKBP52 FK1 peptide ligands appropriate for the control of hormone-dependent physiological mechanisms or of the functioning of the Tau protein. Indeed, it has been shown that FKBP52 is involved in the intraneuronal dynamics of the Tau protein