The role of annealing and fragmentation in human tau aggregation dynamics.
| Autor: | Huseby CJ; From the Interdisciplinary Biophysics Graduate Program., Bundschuh R; From the Interdisciplinary Biophysics Graduate Program.; Departments of Physics, Internal Medicine, and Chemistry and Biochemistry, and., Kuret J; From the Interdisciplinary Biophysics Graduate Program, kuret.3@osu.edu.; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, Ohio 43210. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of biological chemistry [J Biol Chem] 2019 Mar 29; Vol. 294 (13), pp. 4728-4737. Date of Electronic Publication: 2019 Feb 11. |
| DOI: | 10.1074/jbc.RA118.006943 |
| Abstrakt: | Alzheimer's disease pathogenesis is associated with the conversion of monomeric tau protein into filamentous aggregates. Because both toxicity and prion-like spread of pathogenic tau depend in part on aggregate size, the processes that underlie filament formation and size distribution are of special importance. Here, using a combination of biophysical and computational approaches, we investigated the fibrillation dynamics of the human tau isoform 2N4R. We found that tau filaments engage in a previously uncharacterized secondary process involving end-to-end annealing and that rationalization of empirical aggregation data composed of total protomer concentrations and fibril length distributions requires inclusion of this process along with filament fragmentation. We noted that annealing of 2N4R tau filaments is robust, with an intrinsic association rate constant of a magnitude similar to that mediating monomer addition and consistent with diffusion-mediated protein-protein interactions in the absence of long-range attractive forces. In contrast, secondary nucleation on the surface of tau filaments did not detectably contribute to tau aggregation dynamics. These results indicate that tau filament ends engage in a range of homotypic interactions involving monomers, oligomers, and filaments. They further indicate that, in the case of tau protein, fibril annealing and fragmentation along with primary nucleation and elongation are the major processes controlling filament size distribution. (© 2019 Huseby et al.) |
| Databáze: | MEDLINE |
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