Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 27, Pages 8017-8021Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201802490
Keywords
aggregation; amyloid-beta; local dynamics; oligomers; unnatural amino acids
Categories
Funding
- National Institutes of Health [R15GM116006]
- Alzheimer's Association [AARG-17-531423]
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Elucidating local dynamics of protein aggregation is crucial for understanding the mechanistic details of protein amyloidogenesis. Herein, we studied the residue-specific dynamics and local environmental changes of A beta 40 along the course of aggregation by using para-cyanophenylalanine (Phe(CN)) as a fluorescent and vibrational probe. Our results show that the Phe(CN) residues introduced at various positions all exhibited an immediate decay of fluorescence intensity, indicating a relatively synergistic process in early oligomer formation. The fast decreases in the fluorescence intensities of residues19 and 20 in the central hydrophobic core region and residue10 in the N-terminal region suggest that they play crucial roles in the formation of the oligomeric core. The Phe(CN)4 residue exhibits a remarkably slower decrease in fluorescence intensity, implicating its dynamic conformational characteristics in oligomer and fibril formation. Our results also suggest that the N-terminal residues in fibrils are surrounded by a relatively hydrophobic local environment, as opposed to being solvated.
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