Aggregation and Fibril Structure of AβM01–42 and Aβ1–42
| العنوان: | Aggregation and Fibril Structure of AβM01–42 and Aβ1–42 |
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| المؤلفون: | Sara Linse, Robert Silvers, Michael T. Colvin, Robert G. Griffin, Kendra K. Frederick, Angela C. Jacavone, Susan Lindquist |
| المصدر: | Biochemistry. 56:4850-4859 |
| بيانات النشر: | American Chemical Society (ACS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, chemistry.chemical_classification, Methionine, Kinetics, Rational design, Peptide, Plasma protein binding, Fibril, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, Protein structure, chemistry, Magic angle spinning, Biophysics |
| الوصف: | A mechanistic understanding of Aβ aggregation and high-resolution structures of Aβ fibrils and oligomers are vital to elucidating relevant details of neurodegeneration in Alzheimer's disease, which will facilitate the rational design of diagnostic and therapeutic protocols. The most detailed and reproducible insights into structure and kinetics have been achieved using Aβ peptides produced by recombinant expression, which results in an additional methionine at the N-terminus. While the length of the C-terminus is well established to have a profound impact on the peptide's aggregation propensity, structure, and neurotoxicity, the impact of the N-terminal methionine on the aggregation pathways and structure is unclear. For this reason, we have developed a protocol to produce recombinant Aβ1-42, sans the N-terminal methionine, using an N-terminal small ubiquitin-like modifier-Aβ1-42 fusion protein in reasonable yield, with which we compared aggregation kinetics with AβM01-42 containing the additional methionine residue. The data revealed that Aβ1-42 and AβM01-42 aggregate with similar rates and by the same mechanism, in which the generation of new aggregates is dominated by secondary nucleation of monomers on the surface of fibrils. We also recorded magic angle spinning nuclear magnetic resonance spectra that demonstrated that excellent spectral resolution is maintained with both AβM01-42 and Aβ1-42 and that the chemical shifts are virtually identical in dipolar recoupling experiments that provide information about rigid residues. Collectively, these results indicate that the structure of the fibril core is unaffected by N-terminal methionine. This is consistent with the recent structures of AβM01-42 in which M0 is located at the terminus of a disordered 14-amino acid N-terminal tail. |
| تدمد: | 1520-4995 0006-2960 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::89df1bf3ba3bcb10c5463476fa0e14c6 https://doi.org/10.1021/acs.biochem.7b00729 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........89df1bf3ba3bcb10c5463476fa0e14c6 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204995 00062960 |
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