Amyloid Fibril Formation of Arctic Amyloid-β 1-42 Peptide is Efficiently Inhibited by the BRICHOS Domain
| العنوان: | Amyloid Fibril Formation of Arctic Amyloid-β 1-42 Peptide is Efficiently Inhibited by the BRICHOS Domain |
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| المؤلفون: | Zhong, Xueying, Kumar, R., Wang, Y., Biverstål, H., Jegerschöld, Caroline, Koeck, Philip J. B., Johansson, J., Abelein, A., Chen, G. |
| المصدر: | ACS Chemical Biology. 17(8):2201-2211 |
| مصطلحات موضوعية: | Alzheimer, amyloid-β peptide, Arctic, Bri2 BRICHOS, amyloid, amyloid beta protein[1-42], bri2 protein, chaperone, monomer, oligomer, protein, recombinant protein, thioflavine, unclassified drug, amyloid beta protein, peptide, peptide fragment, peptide I, receptor for activated C kinase, Alzheimer disease, amino acid sequence, Article, brichos domain, fluorescence intensity, gene mutation, kinetics, neurotoxicity, protein aggregation, protein domain, chemistry, human, metabolism, Amyloid beta-Peptides, Humans, Molecular Chaperones, Peptide Fragments, Peptides, Receptors for Activated C Kinase |
| الوصف: | Amyloid-β peptide (Aβ) aggregation is one of the hallmarks of Alzheimer's disease (AD). Mutations in Aβ are associated with early onset familial AD, and the Arctic mutant E22G (Aβarc) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of Aβarcby mainly interfering with secondary nucleation. This is qualitatively different from the microscopic inhibition mechanism for the wild-type Aβ, against which Bri2 BRICHOS has a major effect on both secondary nucleation and fibril end elongation. The monomeric Aβ42arcpeptide aggregates into amyloid fibrils significantly faster than wild-type Aβ (Aβ42wt), as monitored by thioflavin T (ThT) binding, but the final ThT intensity was strikingly lower for Aβ42arccompared to Aβ42wtfibrils. The Aβ42arcpeptide formed large aggregates, single-filament fibrils, and multiple-filament fibrils without obvious twists, while Aβ42wtfibrils displayed a polymorphic pattern with typical twisted fibril architecture. Recombinant human Bri2 BRICHOS binds to the Aβ42arcfibril surface and interferes with the macroscopic fibril arrangement by promoting single-filament fibril formation. This study provides mechanistic insights on how BRICHOS efficiently affects the aggressive Aβ42arcaggregation, resulting in both delayed fibril formation kinetics and altered fibril structure. |
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| الوصول الحر: | https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-326796Test https://doi.org/10.1021/acschembio.2c00344Test |
| قاعدة البيانات: | SwePub |
| تدمد: | 15548929 15548937 |
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| DOI: | 10.1021/acschembio.2c00344 |