Přehled

Doctoral study program: Life Sciences (Faculty of Science, Masaryk University)

Research area: structural biology, conformations of proteins, protein-protein interactions, brain disorders

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 towards 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. Special emphasis will be used for the applying of solution NMR spectroscopy for the monitoring of secondary structure propensities and proline conformations within Tau and α-synuclein protein as well as binding epitopes of their selected binding partners.

Recommended literature

  • Kitoka K, Lends A, Kučinskas G, Bula AL, Krasauskas L, Smirnovas V, Zilkova M; Kovacech B, Skrabana R, Hritz J, Jaudzems K*: dGAE(297-391) tau fragment promotes formation of CTE-like full-length tau filaments, Angew. Chem. Int. Ed. 2024, e202407821
  • Crha R., Kozeleková A., Hofrová A., Iľkovičová L., Gašparik N., Kadeřávek P., Hritz J.*: Hiding in plain sight: Complex interaction patterns between Tau and 14-3-3ζ protein variants. Int. J. Biol. Macromol.2024, 266, 130802
  • Lasorsa A., Bera K., Malki I., Dupré E., Cantrelle F., Merzougui H., Sinnaeve D., Hanoulle X., Hritz J.*, Landrieu I.*: Conformational impact of multiple phosphorylations within BIN1 SH3 domain binding site in the proline rich region of Tau protein. Biochemistry 2023, 62, 1631–1642, doi: 10.1021/acs.biochem.2c00717
  • 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
  • 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

Funding

2023 – 2026: Horizont Evropa: HORIZON-WIDERA-2022-ACCESS-04 (ID: 68358): Alzheimer’s Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe (ADDIT-CE)

2024-2027: MŠMT JPND (ID:9F24003): Spatiotemporal transcriptome and proteome analysis of Synuclein pathology in Parkinson’s disease: Identification of cell type-specific vulnerability and tolerance mechanisms (4DPD-Omics)

2020 – 2025: Mobility grant H2020-MSCA-RISE-2019 InterTau (ID: 873127): Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer´s disease (InterTau)

Requirements on candidates

preferable candidate’s background in biophysics/biophysical chemistry, biochemistry, structural or molecular biology

Keywords: Tau protein, a-Syn, intrinsically disordered proteins, phosphorylation, 14-3-3 proteins, NMR spectroscopy, neurodegenerative diseases

Information about the application process: https://www.ceitec.eu/ls-mm-phd/

Application webpage: https://www.ceitec.eu/elucidation-of-conformational-changes-by-nmr-spectroscopy-within-selected-intrinsically-disordered-proteins-relevant-in-neurodegenerative-diseases/t11436

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