Publication details

How does phosphorylation affect interaction between 14-3-3ζ and Tau proteins?

Investor logo
Authors

KOZELEKOVÁ Aneta IĽKOVIČOVÁ Lucia CRHA Radek HOFROVÁ Alena HRITZ Jozef

Year of publication 2024
Type Conference abstract
MU Faculty or unit

Central European Institute of Technology

Citation
Description Phosphorylation is a post-translational modification that affects structure, function, and interactions of proteins. 14-3-3? protein, an abundant human regulatory protein, in non-phosphorylated state exists as a dimer [1]. However, after phosphorylation at Ser58 (pS58), it monomerizes and changes its properties [2, 3]. Hyperphosphorylation of Tau protein, a microtubule-associated protein, causes detachment of Tau from microtubules in neurons and leads to neurodegeneration [4]. Hyperphosphorylated Tau aggregates into neurofibrillary tangles (NFTs) - one of the hallmarks of Alzheimer’s disease (AD). As 14-3-3? proteins were found colocalized in the NFTs [5], their interconnection with Tau in AD needs to be comprehended. In our study, we aimed to compare interaction properties of dimeric 14-3-3? WT and monomeric 14-3-3? pS58 with respect to Tau protein. The interaction with Tau protein phosphorylated by protein kinase A (PKA) was inspected from various points of view. The binding affinity, stoichiometry, and interacting residues were studied using native-PAGE, chemical cross-linking, tandem MS, and NMR spectroscopy. We revealed that phosphorylation of 14-3-3? at Ser58 decreases its affinity to Tau protein and changes binding stoichiometry. Both NMR and cross-linking results suggested that Tau is in contact with 14-3-3? proteins via the proline-rich domain and microtubule-binding domain. Moreover, cross-linking data showed that not only the binding channel of 14-3-3? protein is responsible for Tau binding, but also the outer 14-3-3? protein surface and exposed dimeric interface of monomeric 14-3-3? pS58 are involved. In summary, we provide novel insight into the 14-3-3?+Tau interaction and its regulation by phosphorylation of both partners. 1. V. Obsilova & T. Obsil, Front. Mol. Biosci., 9, (2022), 1-15. 2. A. Kozeleková, A. Náplavová, T. Brom, N. Gašparik, J. Šimek, J. Houser, J. Hritz, Front. Chem., 10, (2022), 1-17. 3. Z. Trošanová, P. Louša, A. Kozeleková, T. Brom, N. Gašparik, J. Tungli, V. Weisová, E. Župa, G. Žoldák, J. Hritz, J. Mol. Biol., 434, (2022), 167479. 4. T. Arendt, J. T. Stieler, M. Holzer, Brain. Res. Bull., 126, (2016), 238-292. 5. R. Layfield, J. Fergusson, A. Aitken, J. Lowe, M. Landon, R. J. Mayer, Neurosci. Lett., 209, (1996), 57-60. This project has received funding from the European Union’s Horizon Europe program under the grant agreement No. 101087124 and from Czech Science Foundation (GF20-05789L). We acknowledge CEITEC Proteomics Core Facility and Josef Dadok National NMR Centre of CIISB, Instruct-CZ Centre, supported by MEYS CR (LM2023042) and European Regional Development Fund-Project „UP CIISB“ (No. CZ.02.1.01/0.0/0.0/18_046/0015974). Computational resources were provided by the e-INFRA CZ project (ID:90254), supported by MEYS CR.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.

More info