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Hsu F, Park G, Guo Z. Key Residues for the Formation of Aβ42 Amyloid Fibrils. ACS Omega. 2018;3(7):8401-8407doi: 10.1021/acsomega.8b00887.
Hsu, F., Park, G., & Guo, Z. (2018). Key Residues for the Formation of Aβ42 Amyloid Fibrils. ACS omega, 3(7), 8401-8407. https://doi.org/10.1021/acsomega.8b00887
Hsu, Frederick, et al. "Key Residues for the Formation of Aβ42 Amyloid Fibrils." ACS omega vol. 3,7 (2018): 8401-8407. doi: https://doi.org/10.1021/acsomega.8b00887
Hsu F, Park G, Guo Z. Key Residues for the Formation of Aβ42 Amyloid Fibrils. ACS Omega. 2018 Jul 31;3(7):8401-8407. doi: 10.1021/acsomega.8b00887. PMID: 30087945; PMCID: PMC6068601.
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ACS Omega. 2018 Jul 31;3(7):8401-8407. doi: 10.1021/acsomega.8b00887.

Key Residues for the Formation of Aβ42 Amyloid Fibrils.

ACS omega

Frederick Hsu, Giovanna Park, Zhefeng Guo

Affiliations

  1. Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, 710 Westwood Plaza, Los Angeles, California 90095, United States.

PMID: 30087945 PMCID: PMC6068601 DOI: 10.1021/acsomega.8b00887

Abstract

Formation of amyloid fibrils by Aβ42 protein is a pathological hallmark of Alzheimer's disease. Aβ42 fibrillization is a nucleation-dependent polymerization process, in which nucleation is the rate-limiting step. Structural knowledge of the fibril nucleus is important to understand the molecular mechanism of Aβ aggregation and is also critical for successful modulation of the fibrillization process. Here, we used a scanning mutagenesis approach to study the role of each residue position in Aβ42 fibrillization kinetics. The side chain we used to replace the native residue is a nitroxide spin label called R1, which was introduced using site-directed spin labeling. In this systematic study, all residue positions of Aβ42 sequence were studied, and we identified six key residues for the Aβ42 fibril formation: H14, E22, D23, G33, G37, and G38. Our results suggest that charges at positions 22 and 23 and backbone flexibilities at positions 33, 37, and 38 play key roles in Aβ42 fibrillization kinetics. Our results also suggest that the formation of a β-strand at residues 15-21 is an important feature in Aβ42 fibril nucleus. In overall evaluation of all of the mutational effects on fibrillization kinetics, we found that the thioflavin T fluorescence at the aggregation plateau is a poor indicator of aggregation rates.

Conflict of interest statement

The authors declare no competing financial interest.

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