Factors influencing compact-extended structure equilibrium in oligomers of Aβ1-40 peptide-an ion mobility mass spectrometry study.
PBN-AR
Instytucja
Instytut Biochemii i Biofizyki Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
EN
Czasopismo
Journal of Molecular Biology
ISSN
0022-2836
EISSN
1089-8638
Wydawca
ACADEMIC PRESS LTD- ELSEVIER SCIENCE
DOI
Rok publikacji
2014
Numer zeszytu
15
Strony od-do
2871-2885
Numer tomu
426
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
EN
Alzheimer's disease;
Aβ1–40 peptide;
collisional cross-section;
ion mobility separation mass spectrometry;
oligomer structure
Streszczenia
Język
EN
Treść
Oligomers formed by amyloid β (Aβ) peptide are widely believed to be the main neurotoxic agent in Alzheimer's disease. Studies discovered a broad variety of oligomeric forms, which display different levels of toxicity. Some of these forms may further assemble into mature fibrils, while other might be off-pathway from conversion to fibrils and assemble into alternative forms. To better understand a relationship between the structure and toxicity of Aβ oligomers, we require systematic characterization and classification of all possible forms, facilitating rational design of the beneficial modifiers of their activity. In previous ion mobility analysis of Aβ1-40 oligomers, we have detected the coexistence of two alternative structural forms (compact and extended) in a pool of low-order Aβ1-40 oligomers. These forms may represent two pathways of the oligomer evolution, leading either to fibrils or to off-pathway oligomers, which are potential candidates for the neurotoxic species. Here, we have analyzed the impact of incubation time, the presence of selected metal ions and the effect of a series of point mutations on mutual population of alternative forms. We have shown that a salt bridge D23K28 provides stabilization of the compact form whereas G25 is required for the existence of the extended form. We have found that binding of metal ions also stabilizes the compact form. These results improve our understanding of the possible molecular mechanism of the bifurcation of structural evolution of non-monomeric Aβ species into an off-fibril pathway, ultimately leading to the formation of potentially neurotoxic species.
Cechy publikacji
Article
Inne
System-identifier
4925
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