Tuesday, May 20, 2008

J. Am. Chem. Soc., 130 (18), 5922–5928, 2008.

Characterization of Alzheimer’s-like Paired Helical Filaments from the Core Domain of Tau Protein Using Solid-State NMR SpectroscopyOvidiu C.
Andronesi, Martin von Bergen, Jacek Biernat, Karsten Seidel, Christian Griesinger, Eckhard Mandelkow, and Marc Baldus

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 β-strands. Combination of through-bond and through-space ssNMR transfer methods with water-edited (15N,13C) and (13C,13C) 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.

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