1. Tau conformational changes induced by phosphorylation, truncation, and 14-3-3 proteins relevant in neurodegenerative diseases
Supervisor: doc. RNDr. Mgr. Jozef Hritz, Ph.D.
Annotation:
The main neuropathological signs of Alzheimer’s disease are associated with the fibrillization of tau protein into neurofibrillary tangles. Studying how different factors influence the formation of protein fibrils is the key to understanding these neurodegenerative processes. The main aim of this PhD project will be the characterization of conformational changes in the formation of tau fibrils due to their truncations, phosphorylation, and interaction with 14-3-3 proteins. An interdisciplinary approach combining biomolecular NMR, biophysical interaction techniques, and computational methods will be applied. The described activities are part of international research projects allowing us to spend part of PhD study in the groups of our collaborators in Europe or North and South America and to learn specific research techniques, there.
Requirements on candidates:
Preferable candidate’s background in biophysics, biochemistry, structural or molecular biology.
Recommended literature:
- Trosanova Z., Lousa P., Kozelekova A., Brom T., Gasparik N., Tungli J., Weisova V., Zupa E., Zoldak G., Hritz J.*: Quantitation of human 14-3-3ζ dimerization and the effect of phosphorylation on dimer-monomer ekvilibria. J. Mol. Biol. 2022, 434, 167479
- Kitoka K., Skrabana R., Gašparik N., Hritz J., Jaudzems K. NMR Studies of Tau Protein in Tauopathies. Front. Mol. Biosci. 2021, 8:761227
- Zapletal, V.; Mládek, A.; Melková, K.; Louša, P.; Nomilner, E.; Jaseňáková, Z.; Kubáň, V.; Makovická, M.; Laníková, A.; Žídek L.; Hritz, J.* Choice of force field for proteins containing structured and intrinsically disordered regions. Biophys. J. 2020, 118, 1621 – 1633
- Louša, P.; Nedozrálová, H.; Župa, E.; Nováček, J.; Hritz, J.*: Phosphorylation of the regulatory domain of human tyrosine hydroxylase 1 monitored using non-uniformly sampled NMR. Biophys. Chem. 2017, 223, 25-29
- Jansen S., Melková K., Trošanová Z., Hanáková K., Zachrdla M., Nováček J., Župa E., Zdráhal Z., Hritz J.*, Žídek L.*: Quantitative Mapping of MAP2c Phosphorylation and 14-3-3ζ Binding Sites Reveals Key Differences Between MAP2c and Tau. J. Biol. Chem. 2017, 292, 6715-6727
Keywords: Tau protein, intrinsically disordered proteins, phosphorylation, 14-3-3 proteins, NMR spectroscopy, neurodegenerative diseases
2. Computational simulations of the conformational changes within Tau protein and its fibrilization
Supervisor: doc. RNDr. Mgr. Jozef Hritz, Ph.D.
Annotation:
The main neuropathological signs of Alzheimer’s disease are associated with the fibrillization of tau protein into neurofibrillary tangles. Studying how different factors influence the formation of protein fibrils is the key to understanding these neurodegenerative processes. The main aim of this PhD project will be computational simulations of conformational changes within the Tau protein and the fibrilization processes. The details of the conformation changes and the fibrilization induced by the phosphorylation, buffer conditions, truncation, or the interaction with the client proteins like 14-3-3s will be studied by molecular dynamics at the atomistic and the coarse-grained level. The obtained theoretical predictions will be validated with the experimental data provided by the biomolecular NMR and the biophysical methods. The described activities are part of international research projects allowing to spend the part of PhD study in the groups of our collaborators in Europe or North and South America and to learn specific research techniques, there.
Requirements on candidates:
Preferable candidate’s background in biophysics, computational chemistry, or physical chemistry.
Recommended literature:
- Trosanova Z., Lousa P., Kozelekova A., Brom T., Gasparik N., Tungli J., Weisova V., Zupa E., Zoldak G., Hritz J.*: Quantitation of human 14-3-3ζ dimerization and the effect of phosphorylation on dimer-monomer ekvilibria. J. Mol. Biol. 2022, 434, 167479
- Zapletal, V.; Mládek, A.; Melková, K.; Louša, P.; Nomilner, E.; Jaseňáková, Z.; Kubáň, V.; Makovická, M.; Laníková, A.; Žídek L.; Hritz, J.* Choice of force field for proteins containing structured and intrinsically disordered regions. Biophys. J. 2020, 118, 1621 – 1633
- Pavlíková Přecechtělová J., Mládek A., Zapletal V., Hritz J., Quantum Chemical Calculations of NMR Chemical Shifts in Phosphorylated Intrinsically Disordered Proteins, JCTC 2019, 15, 5642-5658
- Jandova Z; Trosanova Z.; Weisova V.; Oostenbrink C., Hritz J.*: Free energy calculations on the stability of the 14-3-3zéta protein. BBA - Proteins and Proteomics, 2018, 1866, 442-450
- Nagy G., Oostenbrink C., Hritz J.*: Exploring the Binding Pathways of the 14-3-3z Protein: Structural and Free-Energy Profiles Revealed by Hamiltonian Replica Exchange Molecular Dynamics with Distance Field Distance Restraints. PLoS ONE 2017,12(7), e0180633
Keywords: computational simulations, molecular dynamics, coarse-grained simulations, Tau protein, neurodegenerative diseases
