Dataset Information

Amyloid Fibril Formation of Arctic Amyloid-β 1-42 Peptide is Efficiently Inhibited by the BRICHOS Domain.

ABSTRACT: 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 (Aβ^arc) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of Aβ^arc by 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 Aβ42^arc peptide aggregates into amyloid fibrils significantly faster than wild-type Aβ (Aβ42^wt), as monitored by thioflavin T (ThT) binding, but the final ThT intensity was strikingly lower for Aβ42^arc compared to Aβ42^wt fibrils. The Aβ42^arc peptide formed large aggregates, single-filament fibrils, and multiple-filament fibrils without obvious twists, while Aβ42^wt fibrils displayed a polymorphic pattern with typical twisted fibril architecture. Recombinant human Bri2 BRICHOS binds to the Aβ42^arc fibril 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 Aβ42^arc aggregation, resulting in both delayed fibril formation kinetics and altered fibril structure.

SUBMITTER: Zhong X

PROVIDER: S-EPMC9396614 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Amyloid Fibril Formation of Arctic Amyloid-β 1-42 Peptide is Efficiently Inhibited by the BRICHOS Domain.

Zhong Xueying X Kumar Rakesh R Wang Yu Y Biverstål Henrik H Ingeborg Jegerschöld Caroline C J B Koeck Philip P Johansson Jan J Abelein Axel A Chen Gefei G

ACS chemical biology 20220725 8

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 (Aβ<sup>arc</sup>) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of Aβ<sup>arc</sup> by mainly interfering with secondary nucleation. This is qualitatively different from the microscopic inhibition mechanism for the ...[more]

PMID: 35876740

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Project description:The inherent tendency of proteins to convert from their native states into amyloid aggregates is associated with a range of human disorders, including Alzheimer's and Parkinson's diseases. In that sense, the use of small molecules as probes for the structural and toxic mechanism related to amyloid aggregation has become an active area of research. Compared with other compounds, the structural and molecular basis behind the inhibitory interaction of phthalocyanine tetrasulfonate (PcTS) with proteins such as αS and tau has been well established, contributing to a better understanding of the amyloid aggregation process in these proteins. We present here the structural characterization of the binding of PcTS and its Cu(II) and Zn(II)-loaded forms to the amyloid β-peptide (Aβ) and the impact of these interactions on the peptide amyloid fibril assembly. Elucidation of the PcTS binding modes to Aβ40 revealed the involvement of specific aromatic and hydrophobic interactions in the formation of the Aβ40-PcTS complex, ascribed to a binding mode in which the planarity and hydrophobicity of the aromatic ring system in the phthalocyanine act as main structural determinants for the interaction. Our results demonstrated that formation of the Aβ40-PcTS complex does not interfere with the progression of the peptide toward the formation of amyloid fibrils. On the other hand, conjugation of Zn(II) but not Cu(II) at the center of the PcTS macrocyclic ring modified substantially the binding profile of this phthalocyanine to Aβ40 and became crucial to reverse the effects of metal-free PcTS on the fibril assembly of the peptide. Overall, our results provide a firm basis to understand the structural rules directing phthalocyanine-protein interactions and their implications on the amyloid fibril assembly of the target proteins; in particular, our results contradict the hypothesis that PcTS might have similar mechanisms of action in slowing the formation of a variety of pathological aggregates.

Dataset Information

Amyloid Fibril Formation of Arctic Amyloid-β 1-42 Peptide is Efficiently Inhibited by the BRICHOS Domain.

Publications

Amyloid Fibril Formation of Arctic Amyloid-β 1-42 Peptide is Efficiently Inhibited by the BRICHOS Domain.

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