| Autor: |
Majewski J; Division of Molecular and Cellular Biology, National Science Foundation, Alexandria, VA, 22314, USA.; Department of Chemical and Biological Engineering and Center for Biomedical Engineering, University of New Mexico, Albuquerque, NM, 87131, USA.; Theoretical Biology and Biophysics Division, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA., Jones EM; Nanoscience and Microsystems Engineering Graduate Program, University of New Mexico, Albuquerque, NM, 87131, USA.; Department of Chemical and Biological Engineering and Center for Biomedical Engineering, University of New Mexico, Albuquerque, NM, 87131, USA., Vander Zanden CM; Department of Chemical and Biological Engineering and Center for Biomedical Engineering, University of New Mexico, Albuquerque, NM, 87131, USA.; Department of Chemistry and Biochemistry, University of Colorado at Colorado Springs, Colorado Springs, CO, 80918, USA., Biernat J; Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany.; CAESAR Research Center, 53175, Bonn, Germany., Mandelkow E; Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany.; CAESAR Research Center, 53175, Bonn, Germany., Chi EY; Department of Chemical and Biological Engineering and Center for Biomedical Engineering, University of New Mexico, Albuquerque, NM, 87131, USA. evachi@unm.edu. |
| Abstrakt: |
The aggregation of the intrinsically disordered tau protein into highly ordered β-sheet-rich fibrils is implicated in the pathogenesis of a range of neurodegenerative disorders. The mechanism of tau fibrillogenesis remains unresolved, particularly early events that trigger the misfolding and assembly of the otherwise soluble and stable tau. We investigated the role the lipid membrane plays in modulating the aggregation of three tau variants, the largest isoform hTau40, the truncated construct K18, and a hyperphosphorylation-mimicking mutant hTau40/3Epi. Despite being charged and soluble, the tau proteins were also highly surface active and favorably interacted with anionic lipid monolayers at the air/water interface. Membrane binding of tau also led to the formation of a macroscopic, gelatinous layer at the air/water interface, possibly related to tau phase separation. At the molecular level, tau assembled into oligomers composed of ~ 40 proteins misfolded in a β-sheet conformation at the membrane surface, as detected by in situ synchrotron grazing-incidence X-ray diffraction. Concomitantly, membrane morphology and lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein tau's inherent surface activity and favorable interactions with anionic lipids drive tau-membrane association, inducing misfolding and self-assembly of the disordered tau into β-sheet-rich oligomers that subsequently seed fibrillation and deposition into diseased tissues. |
