title: Characterization of Alzheimer's-like paired helical filaments from the core domain of tau protein using solid-state NMR spectroscopy.
abstract: The polymerization of the microtubule-associated protein tau into paired helical filaments (PHFs) represents one of the hallmarks of Alzheimer's disease. We employed solid-state nuclear magnetic resonance (NMR) to investigate the structure and dynamics of PHFs formed in vitro by the three-repeat-domain (K19) of protein tau, representing the core of Alzheimer PHFs. While N and C termini of tau monomers in PHFs are highly dynamic and solvent-exposed, the rigid segment consists of three major beta-strands. Combination of through-bond and through-space ssNMR transfer methods with water-edited ((15)N, (13)C) and ((13)C, (13)C) correlation experiments suggests the existence of a fibril core that is largely built by repeat unit R3, flanked by surface-exposed units R1 and R4. Solid-state NMR, circular dichroism, and the fibrillization behavior of a K19 mutant furthermore indicate that electrostatic interactions play a central role in stabilizing the K19 PHFs.
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Andronesi
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Karsten
authors.initials: K
authors.lastname: Seidel
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Marc
authors.initials: M
authors.lastname: Baldus
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D002942:Circular Dichroism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D016875:tau Proteins