title: Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure.
abstract: The microtubule-associated protein tau is a natively unfolded protein in solution, yet it is able to polymerize into the ordered paired helical filaments (PHF) of Alzheimer's disease. In the splice isoforms lacking exon 10, this process is facilitated by the formation of beta-structure around the hexapeptide motif PHF6 ((306)VQIVYK(311)) encoded by exon 11. We have investigated the structural requirements for PHF polymerization in the context of adult tau isoforms containing four repeats (including exon 10). In addition to the PHF6 motif there exists a related PHF6* motif ((275)VQIINK(280)) in the repeat encoded by the alternatively spliced exon 10. We show that this PHF6* motif also promotes aggregation by the formation of beta-structure and that there is a cross-talk between the two hexapeptide motifs during PHF aggregation. We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the hexapeptide motifs.
authors.affiliation: Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: von Bergen
authors.forename: S
authors.initials: S
authors.lastname: Barghorn
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Marx
authors.forename: J
authors.initials: J
authors.lastname: Biernat
authors.forename: E M
authors.initials: EM
authors.lastname: Mandelkow
authors.forename: E
authors.initials: E
authors.lastname: Mandelkow
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001704:Biopolymers; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D011487:Protein Conformation; D017550:Spectroscopy, Fourier Transform Infrared; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000648:ultrastructure
chemical_list: D001704:Biopolymers; D009842:Oligopeptides; D016875:tau Proteins