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Structural and microtubule binding properties of tau mutants of frontotemporal dementias

Daniela Fischer1, Marco D Mukrasch, Martin von Bergen

  • 1Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.

Biochemistry
|February 15, 2007
PubMed

Insights

Mutations causing frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) alter tau protein structure. These changes weaken tau binding to microtubules but not to heparin, impacting neurofibrillary tangle formation.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Genetics

Background:

  • Mutations in the tau gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17).
  • Neurofibrillary inclusions are a hallmark of FTDP-17, involving the tau protein.

Purpose of the Study:

  • To characterize the conformational properties of two FTDP-17 tau mutants (P301L and DeltaK280).
  • To investigate how these mutations affect tau's binding to polyanions and microtubules.

Main Methods:

  • High-resolution characterization using multidimensional NMR spectroscopy.
  • Analysis of tau mutant binding affinities to heparin and microtubules.

Main Results:

  • Mutations did not significantly increase beta-structure in monomeric tau but promoted it during aggregation.
  • Local structural changes were observed in the second repeat of tau.
  • Binding to heparin was only weakly affected, while binding to microtubules was significantly decreased.

Conclusions:

  • Tau's reversible binding to microtubules involves specific interactions.
  • These specific interactions are not essential for tau's binding to polyanions like heparin.
  • Understanding these interactions is crucial for FTDP-17 pathogenesis research.

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