title: The "jaws" of the tau-microtubule interaction.
abstract: Tau is the major microtubule-associated protein in neuronal axons. It aggregates into "neurofibrillary tangles" during the course of Alzheimer disease. Binding to microtubules and microtubule assembly requires the "repeat domain" in the C-terminal half of Tau, as well as the two regions flanking the repeats. Here we report the NMR characterization of a 198-residue Tau fragment composed of the four tandem repeats and the flanking domains and containing the full microtubule binding and assembly activity of Tau. NMR secondary chemical shifts and dipolar couplings detect the highest propensity for beta-structure within the four-repeat region, whereas the flanking domains are largely random coil, with an increased rigidity in the proline-rich region. Chemical shift perturbation experiments identify two motifs in the upstream flanking domain, (225)KVAVVRT(231) and (243)LQTA(246), and one downstream of the repeats, (370)KIETHKTFREN(380), which strongly contribute to the binding to the acidic outside of microtubules, as well as to the binding of other polyanions such as heparin. This is consistent with the "jaws" model of Tau-microtubule interactions and highlights the importance of the regions flanking the repeats for both microtubule binding and pathological Tau aggregation.
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen.
authors.forename: Marco D
authors.initials: MD
authors.lastname: Mukrasch
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Daniela
authors.initials: D
authors.lastname: Fischer
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; D000838:Anions; D006801:Humans; D007477:Ions; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D000838:Anions; D007477:Ions; D011994:Recombinant Proteins; D016875:tau Proteins