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Role of Hydrophobicity at the N-Terminal Region of Aβ42 in Secondary Nucleation
- Source :
- ACS Chemical Neuroscience. 13:3477-3487
- Publication Year :
- 2022
- Publisher :
- American Chemical Society (ACS), 2022.
-
Abstract
- The self-assembly of the amyloid β 42 (Aβ42) peptide is linked to Alzheimer's disease, and oligomeric intermediates are linked to neuronal cell death during the pathology of the disease. These oligomers are produced prolifically during secondary nucleation, by which the aggregation of monomers is catalyzed on fibril surfaces. Significant progress has been made in understanding the aggregation mechanism of Aβ42; still, a detailed molecular-level understanding of secondary nucleation is lacking. Here, we explore the role of four hydrophobic residues on the unstructured N-terminal region of Aβ42 in secondary nucleation. We create eight mutants with single substitutions at one of the four positions─Ala2, Phe4, Tyr10, and Val12─to decrease the hydrophobicity at respective positions (A2T, A2S, F4A, F4S, Y10A, Y10S, V12A, and V12S) and one mutant (Y10F) to remove the polar nature of Tyr10. Kinetic analyses of aggregation data reveal that the hydrophobicity at the N-terminal region of Aβ42, especially at positions 10 and 12, affects the rate of fibril mass generated via secondary nucleation. Cryo-electron micrographs reveal that most of the mutants with lower hydrophobicity form fibrils that are markedly longer than WT Aβ42, in line with the reduced secondary nucleation rates for these peptides. The dominance of secondary nucleation, however, is still retained in the aggregation mechanism of these mutants because the rate of primary nucleation is even more reduced. This highlights that secondary nucleation is a general phenomenon that is not dependent on any one particular feature of the peptide and is rather robust to sequence perturbations.
Details
- ISSN :
- 19487193
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- ACS Chemical Neuroscience
- Accession number :
- edsair.doi.dedup.....07d302d3d6c24285ba18acf7b40a8f94