This title appears in the Scientific Report :
2017
Please use the identifier:
http://dx.doi.org/10.1016/j.bpj.2017.03.007 in citations.
Pyroglutamate-Modified Amyloid- β (3–42) Shows α -Helical Intermediates before Amyloid Formation
Pyroglutamate-Modified Amyloid- β (3–42) Shows α -Helical Intermediates before Amyloid Formation
Pyroglutamate-modified amyloid-β (pEAβ) has been described as a relevant Aβ species in Alzheimer’s-disease-affected brains, with pEAβ (3–42) as a dominant isoform. Aβ (1–40) and Aβ (1–42) have been well characterized under various solution conditions, including aqueous solutions containing trifluoro...
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Personal Name(s): | Dammers, Christina |
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Reiss, Kerstin / Gremer, Lothar / Lecher, Justin / Ziehm, Tamar / Stoldt, Matthias / Schwarten, Melanie / Willbold, Dieter (Corresponding author) | |
Contributing Institute: |
Strukturbiochemie; ICS-6 |
Published in: | Biophysical journal, 112 (2017) 8, S. 1621 - 1633 |
Imprint: |
Cambridge, Mass.
Cell Press
2017
|
DOI: |
10.1016/j.bpj.2017.03.007 |
PubMed ID: |
28445753 |
Document Type: |
Journal Article |
Research Program: |
Physical Basis of Diseases |
Publikationsportal JuSER |
Pyroglutamate-modified amyloid-β (pEAβ) has been described as a relevant Aβ species in Alzheimer’s-disease-affected brains, with pEAβ (3–42) as a dominant isoform. Aβ (1–40) and Aβ (1–42) have been well characterized under various solution conditions, including aqueous solutions containing trifluoroethanol (TFE). To characterize structural properties of pEAβ (3–42) possibly underlying its drastically increased aggregation propensity compared to Aβ (1–42), we started our studies in various TFE-water mixtures and found striking differences between the two Aβ species. Soluble pEAβ (3–42) has an increased tendency to form β-sheet-rich structures compared to Aβ (1–42), as indicated by circular dichroism spectroscopy data. Kinetic assays monitored by thioflavin-T show drastically accelerated aggregation leading to large fibrils visualized by electron microscopy of pEAβ (3–42) in contrast to Aβ (1–42). NMR spectroscopy was performed for backbone and side-chain chemical-shift assignments of monomeric pEAβ (3–42) in 40% TFE solution. Although the difference between pEAβ (3–42) and Aβ (1–42) is purely N-terminal, it has a significant impact on the chemical environment of >20% of the total amino acid residues, as revealed by their NMR chemical-shift differences. Freshly dissolved pEAβ (3–42) contains two α-helical regions connected by a flexible linker, whereas the N-terminus remains unstructured. We found that these α-helices act as a transient intermediate to β-sheet and fibril formation of pEAβ (3–42). |