Structural and microtubule binding properties of tau mutants of frontotemporal dementias.
Several mutations in the gene encoding the microtubule-associated protein tau are responsible for the formation of neurofibrillary inclusions in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here we present the high-resolution characterization of the conformational properties of two FTDP-17 mutants of the four-repeat domain of tau, P301L and DeltaK280, and their properties for binding to polyanions and microtubules. Multidimensional NMR spectroscopy shows that the mutations do no lead to a significant increase in the level of beta-structure in their monomeric state, even though the mutations strongly promote beta-structure during aggregation. However, local structural changes are induced in the second repeat. These changes only weakly affect the binding to the polyanion heparin, which promotes paired helical filament formation. The extent of binding to microtubules, however, is strongly decreased. Our results demonstrate that the reversible binding of tau to microtubules involves specific interactions, which are not essential for binding to polyanions.
Fischer
Daniela
D
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Mukrasch
Marco D
MD
von Bergen
Martin
M
Klos-Witkowska
Aleksandra
A
Biernat
Jacek
J
Griesinger
Christian
C
Mandelkow
Eckhard
E
Zweckstetter
Markus
M
D003704:Dementia / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D000071228:Polyelectrolytes; D011108:Polymers / Q000378:metabolism; D017433:Protein Structure, Secondary; D012965:Sodium Chloride / Q000494:pharmacology; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; D000071228:Polyelectrolytes; D011108:Polymers; D012965:Sodium Chloride; D016875:tau Proteins