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Ubiquitin binds the amyloid β peptide and interferes with its clearance pathways

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Abstract

Several lines of evidence point to a compromised proteostasis associated with a reduction of the Ubiquitin Proteasome System (UPS) activity in patients affected by Alzheimer's Disease (AD) and suggest that the amyloid β peptide (Aβ) is an important player in the game. Inspired also by many reports, underlining the presence of ubiquitin (Ub) in the amyloid plaques of AD brains, here we set out to test whether Ub may bind the Aβ peptide and have any effect on its clearance pathways. By using an integrated array of MALDI-TOF/UPLC-HRMS, fluorescence, NMR, SPR, Microscale Thermophoresis (MST) and molecular dynamics studies, we consistently demonstrated that Aβ40 binds Ub with a 1 : 1 stoichiometry and Kd in the high micromolar range. In particular, we show that the N-terminal domain of the Aβ peptide (through residues D1, E3 and R5) interacts with the C-terminal tail of Ub (involving residues K63 and E64), inducing the central region of Aβ (14HQKLVFFAEDVGSNK28) to adopt a mixed α-helix/β-turn structure. ELISA assays, carried out in neuroblastoma cell lysates, suggest that Aβ competitively binds Ub also in the presence of the entire pool of cytosolic Ub binding proteins. Ub-bound Aβ has a lower tendency to aggregate into amyloid-like fibrils and is more slowly degraded by the Insulin Degrading Enzyme (IDE). Finally, we observe that the water soluble fragment Aβ1–16 significantly inhibits Ub chain growth reactions. These results evidence how the non-covalent interaction between Aβ peptides and Ub may have relevant effects on the regulation of the upstream events of the UPS and pave the way to future in vivo studies addressing the role played by Aβ peptide in the malfunction of proteome maintenance occurring in AD.

Graphical abstract: Ubiquitin binds the amyloid β peptide and interferes with its clearance pathways

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Publication details

The article was received on 31 Jul 2018, accepted on 09 Jan 2019 and first published on 10 Jan 2019


Article type: Edge Article
DOI: 10.1039/C8SC03394C
Citation: Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
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    Ubiquitin binds the amyloid β peptide and interferes with its clearance pathways

    F. Bellia, V. Lanza, S. García-Viñuales, I. M. M. Ahmed, A. Pietropaolo, C. Iacobucci, G. Malgieri, G. D'Abrosca, R. Fattorusso, V. G. Nicoletti, D. Sbardella, G. R. Tundo, M. Coletta, L. Pirone, E. Pedone, D. Calcagno, G. Grasso and D. Milardi, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C8SC03394C

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