The structure of microtubule-bound tau

• Applicant: Professor Dr. Markus Zweckstetter
• Subject Area: Structural Biology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221226297

• Final Report Year: 2018

Final Report Abstract

In this project, we have provided novel molecular level information about the interaction of the microtubule-associated protein tau, which plays an important role in Alzheimer’s disease and several other neurodegenerative diseases termed tauopathies, with soluble tubulin, microtubules and filamentous actin. In 2018, a model of the repeat region of tau with microtubules was proposed by the Nogales lab on the basis of cryo-electron microscopy in combination with molecular modeling. This model confirmed our results with respect to the binding of tau to the interface between tubulin heterodimers, but lacks parts of tau such as the proline-rich region, which are essential for productive binding of tau to microtubules. Thus, further high-resolution studies are required to understand the structure of tau bound to microtubules and filamentous actin, including the influence of disease-associated mutations and post-translational modifications of the tau protein and their influence on the interaction of tau with the cytoskeleton.

Publications

• Folding of the Tau Protein on Microtubules. Angew Chem Int Ed Engl 54, 10347-51 (2015)
  Kadavath, H., Jaremko, M., Jaremko, L., Biernat, J., Mandelkow, E. & Zweckstetter, M.
  
• Small Molecules Detected by Second-Harmonic Generation Modulate the Conformation of Monomeric alpha- Synuclein and Reduce Its Aggregation in Cells. J Biol Chem 290, 27582-93 (2015)
  Moree, B., Yin, G., Lazaro, D.F., Munari, F., Strohaker, T., Giller, K., Becker, S., Outeiro, T.F., Zweckstetter, M. & Salafsky, J.
  
• Structural Impact of Tau Phosphorylation at Threonine 231. Structure 23, 1448-58 (2015)
  Schwalbe, M., Kadavath, H., Biernat, J., Ozenne, V., Blackledge, M., Mandelkow, E. & Zweckstetter, M.
  
• Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc Natl Acad Sci USA 112, 7501-6 (2015)
  Kadavath, H., Hofele, R.V., Biernat, J., Kumar, S., Tepper, K., Urlaub, H., Mandelkow, E. & Zweckstetter, M.
  
• Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau. Nat Commun 8, 1981 (2017)
  Cabrales Fontela, Y., Kadavath, H., Biernat, J., Riedel, D., Mandelkow, E. & Zweckstetter, M.
  
• The Binding Mode of a Tau Peptide with Tubulin. Angew Chem Int Ed Engl 57, 3246-3250 (2018)
  Kadavath, H., Cabrales Fontela, Y., Jaremko, M., Jaremko, L., Overkamp, K., Biernat, J., Mandelkow, E. & Zweckstetter, M.