AI Article Synopsis
- Several point mutations can alter protein structure and dynamics, impacting the behavior of amyloidogenic proteins linked to neurodegenerative diseases, particularly affecting their fibrillation kinetics.
- Researchers designed specific mutant candidates to inhibit the fibrillation of amyloid-β by analyzing its point mutants through a series of steps, which resulted in reduced aggregation toxicity.
- A combination of techniques such as small-angle X-ray scattering and mass spectrometry was used to investigate the structural basis for this inhibition, offering new insights into how to modulate amyloid aggregation through structural understanding.
Article Abstract
Several point mutations can modulate protein structure and dynamics, leading to different natures. Especially in the case of amyloidogenic proteins closely related to neurodegenerative diseases, structural changes originating from point mutations can affect fibrillation kinetics. Herein, we rationally designed mutant candidates to inhibit the fibrillation process of amyloid-β with its point mutants through multistep analyses. Our results showed that the designed mutants induced kinetic self-assembly suppression and reduced the toxicity of the aggregate. A multidisciplinary biophysical approach with small-angle X-ray scattering, ion mobility-mass spectrometry, mass spectrometry, and additional experiments was performed to reveal the structural basis associated with the inhibition of fibril formation. The structure-based design of the mutants with suppressed self-assembly performed in this study could provide a different perspective for modulating amyloid aggregation based on the structural understanding of the intrinsically disordered proteins.
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| http://dx.doi.org/10.1021/jacs.1c10173 | DOI Listing |
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