Distinct Effects of Zn2+, Cu2+, Fe3+, and Al3+ on Amyloid-beta Stability, Oligomerization, and Aggregation
Resource
JOURNAL OF BIOLOGICAL CHEMISTRY, 286(11), 9646-9656
Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Journal Volume
286
Journal Issue
11
Pages
9646-9656
Date Issued
2011
Date
2011
Author(s)
Chen, Wei-Ting
Liao, Yi-Hung
Yu, Hui-Ming
Cheng, Irene H.
Chen, Yun-Ru
Abstract
Abnormally high concentrations of Zn2+, Cu2+, and Fe3+ are present along with amyloid-β (Aβ) in the senile plaques in Alzheimer disease, where Al3+ is also detected. Aβ aggregation is the key pathogenic event in Alzheimer disease, where Aβ oligomers are the major culprits. The fundamental mechanism of these metal ions on Aβ remains elusive. Here, we employ 4,4′-Bis(1-anilinonaphthalene 8-sulfonate) and tyrosine fluorescence, CD, stopped flow fluorescence, guanidine hydrochloride denaturation, and photo-induced cross-linking to elucidate the effect of Zn2+, Cu2+, Fe3+, and Al3+ on Aβ at the early stage of the aggregation. Furthermore, thioflavin T assay, dot blotting, and transmission electron microscopy are utilized to examine Aβ aggregation. Our results show that Al3+ and Zn 2+, but not Cu2+ and Fe3+, induce larger hydrophobic exposures of Aβ conformation, resulting in its significant destabilization at the early stage. The metal ion binding induces Aβ conformational changes with micromolar binding affinities and millisecond binding kinetics. Cu2+ and Zn2+ induce similar assembly of transiently appearing Aβ oligomers at the early state. During the aggregation, we found that Zn2+ exclusively promotes the annular protofibril formation without undergoing a nucleation process, whereas Cu 2+ and Fe3+ inhibit fibril formation by prolonging the nucleation phases. Al3+ also inhibits fibril formation; however, the annular oligomers co-exist in the aggregation pathway. In conclusion, Zn 2+, Cu2+, Fe3+, and Al3+ adopt distinct folding and aggregation mechanisms to affect Aβ, where Aβ destabilization promotes annular protofibril formation. Our study facilitates the understanding of annular Aβ oligomer formation upon metal ion binding. ? 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
SDGs
Other Subjects
Aggregation mechanism; Alzheimer disease; Binding affinities; Binding kinetics; Conformational change; Dot-blotting; Fibril formation; Guanidine hydrochloride; High concentration; Metal ion binding; Nucleation phasis; Nucleation process; Photo-induced; Senile plaques; Stopped flow; Thioflavin T; Aluminum; Amino acids; Binding energy; Fluorescence; Glycoproteins; Metal ions; Neurodegenerative diseases; Nucleation; Oligomerization; Oligomers; Transmission electron microscopy; Zinc; aluminum; amyloid beta protein; copper ion; iron; zinc ion; amyloid; amyloid precursor protein; APP protein, human; copper; zinc; article; conformational transition; controlled study; hydrophobicity; oligomerization; priority journal; protein aggregation; protein binding; protein cleavage; protein conformation; protein cross linking; protein denaturation; protein stability; stoichiometry; transmission electron microscopy; chemistry; human; protein multimerization; protein stability; ultrastructure; Aluminum; Amyloid; Amyloid beta-Protein Precursor; Copper; Humans; Iron; Protein Multimerization; Protein Stability; Zinc
Type
journal article
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