title: Sites of tau important for aggregation populate {beta}-structure and bind to microtubules and polyanions.
abstract: The aggregation of the microtubule-associated tau protein and formation of "neurofibrillary tangles" is one of the hallmarks of Alzheimer disease. The mechanisms underlying the structural transition of innocuous, natively unfolded tau to neurotoxic forms and the detailed mechanisms of binding to microtubules are largely unknown. Here we report the high-resolution characterization of the repeat domain of soluble tau using multidimensional NMR spectroscopy. NMR secondary chemical shifts detect residual beta-structure for 8-10 residues at the beginning of repeats R2-R4. These regions correspond to sequence motifs known to form the core of the cross-beta-structure of tau-paired helical filaments. Chemical shift perturbation studies show that polyanions, which promote paired helical filament aggregation, as well as microtubules interact with tau through positive charges near the ends of the repeats and through the beta-forming motifs at the beginning of repeats 2 and 3. The high degree of similarity between the binding of polyanions and microtubules supports the hypothesis that stable microtubules prevent paired helical filament formation by blocking the tau-polyanion interaction sites, which are crucial for paired helical filament formation.
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Marco D
authors.initials: MD
authors.lastname: Mukrasch
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000838:Anions; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008239:Lysine; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000737:chemistry*; D008969:Molecular Sequence Data; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000378:metabolism; D000071228:Polyelectrolytes; D011108:Polymers / Q000737:chemistry*; D011485:Protein Binding; D017510:Protein Folding; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013552:Swine; D013696:Temperature; D014404:Tubulin / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D000838:Anions; D008239:Lysine; D000071228:Polyelectrolytes; D011108:Polymers; D020033:Protein Isoforms; D014404:Tubulin; D016875:tau Proteins