Journal article
Elucidating the Role of Hydroxylated Phenylalanine in the Formation and Structure of Cross-Linked Aβ Oligomers
The journal of physical chemistry. B, v 123(5), pp 1068-1084
07 Feb 2019
PMID: 30642171
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Amyloid β-protein (Aβ) oligomers play a seminal role in Alzheimer's disease (AD). Cross-linking (X-linking), which can be used to determine Aβ oligomer size distributions experimentally, was reported to stabilize Aβ oligomers. Aβ oligomers X-linked in the presence of copper and hydrogen peroxide may represent the proximate neurotoxic species in AD. Our previous computational study demonstrated that X-linking of Aβ
and Aβ
oligomers via tyrosines alone cannot explain experimental findings. Here, we explore three plausible X-linking mechanisms, which involve, in addition to tyrosine, also lysine (mechanism 1), histidine (mechanism 2), and hydroxylated phenylalanine (mechanism 3). By examining the effect of X-linking on oligomer size distributions, we show that only mechanism 3 is consistent with experimental data. Our findings provide important insights into the two-step X-linking via mechanism 3, which consists of a simple covalent bonding via tyrosines in the presence of hydroxylated phenylalanines, followed by covalent bonding among tyrosines and hydroxylated phenylalanines. Structural analysis of X-linked Aβ oligomers revealed increased solvent exposure at the N-terminal region, which was previously associated with increased oligomer toxicity. Our results elucidate a potentially important role of phenylalanine hydroxylation and increased toxicity of Aβ oligomers induced by X-linking.
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Details
- Title
- Elucidating the Role of Hydroxylated Phenylalanine in the Formation and Structure of Cross-Linked Aβ Oligomers
- Creators
- Shuting Zhang - Drexel UniversityDillion M Fox - Drexel UniversityBrigita Urbanc - Drexel University
- Publication Details
- The journal of physical chemistry. B, v 123(5), pp 1068-1084
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000458348400012
- Scopus ID
- 2-s2.0-85061123811
- Other Identifier
- 991019168329904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Physical