Počet záznamů: 1  

Phosphorylated full-length Tau interacts with 14-3-3 proteins via two short phosphorylated sequences, each occupying a binding groove of 14-3-3 dimer

  1. 1.
    0541623 - FGÚ 2022 RIV GB eng J - Článek v odborném periodiku
    Neves, J. F. - Petrvalská, Olivia - Bosica, F. - Cantrelle, F. X. - Merzougui, H. - O'Mahony, G. - Hanoulle, X. - Obšil, Tomáš - Landrieu, I.
    Phosphorylated full-length Tau interacts with 14-3-3 proteins via two short phosphorylated sequences, each occupying a binding groove of 14-3-3 dimer.
    FEBS Journal. Roč. 288, č. 6 (2021), s. 1918-1934. ISSN 1742-464X. E-ISSN 1742-4658
    Institucionální podpora: RVO:67985823
    Klíčová slova: 14‐3‐3 proteins * Alzheimer’s disease * analytical ultracentrifugation * NMR spectroscopy * protein–protein interactions * Tau protein
    Obor OECD: Biochemistry and molecular biology
    Impakt faktor: 5.622, rok: 2021
    Způsob publikování: Open access
    https://doi.org/10.1111/febs.15574

    Protein-protein interactions (PPIs) remain poorly explored targets for the treatment of Alzheimer's disease. The interaction of 14-3-3 proteins with Tau was shown to be linked to Tau pathology. This PPI is therefore seen as a potential target for Alzheimer's disease. When Tau is phosphorylated by PKA (Tau-PKA), several phosphorylation sites are generated, including two known 14-3-3 binding sites, surrounding the phosphorylated serines 214 and 324 of Tau. The crystal structures of 14-3-3 in complex with peptides surrounding these Tau phosphosites show that both these motifs are anchored in the amphipathic binding groove of 14-3-3. However, in the absence of structural data with the full-length Tau protein, the stoichiometry of the complex or the interface and affinity of the partners is still unclear. In this work, we addressed these points, using a broad range of biophysical techniques. The interaction of the long and disordered Tau-PKA protein with 14-3-3 sigma is restricted to two short sequences, containing phosphorylated serines, which bind in the amphipathic binding groove of 14-3-3 sigma. Phosphorylation of Tau is fundamental for the formation of this stable complex, and the affinity of the Tau-PKA/14-3-3 sigma interaction is in the 1-10 micromolar range. Each monomer of the 14-3-3 sigma dimer binds one of two different phosphorylated peptides of Tau-PKA, suggesting a 14-3-3/Tau-PKA stoichiometry of 2 : 1, confirmed by analytical ultracentrifugation. These results contribute to a better understanding of this PPI and provide useful insights for drug discovery projects aiming at the modulation of this interaction.
    Trvalý link: http://hdl.handle.net/11104/0319156

     
     
Počet záznamů: 1