| Autor: |
Brigita Urbanc, David B. Teplow, Luis Cruz, Alfonso Lam, Gal Bitan |
| Jazyk: |
angličtina |
| Předmět: |
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| Zdroj: |
Biophysical Journal. (3):219a |
| ISSN: |
0006-3495 |
| DOI: |
10.1016/j.bpj.2008.12.1913 |
| Popis: |
Amyloid b-protein (Ab) exists in two main alloforms, Ab40 and Ab42, of which Ab42 is linked particularly strongly to Alzheimer's disease (AD). Prior computational work demonstrated that the ab initio discrete molecular dynamics approach with an intermediate-resolution protein model captures biologically relevant differences between Ab40 and Ab42 folding and oligomerization. In the present work we apply the same approach to explore the relationship between the structure and toxicity. Assuming that Ab42 oligomers are more toxic than oligomers formed by Ab40, our structural analysis indicates that the solvent accessible surface area (SASA) in the N-terminal region of Ab42 oligomers is significantly higher than that of Ab40 oligomers. We then investigate effects of the C-terminal fragment (CTF), which was shown to attenuate Ab42 oligomer toxicity in a cell culture, on Ab42 oligomerization. Our results indicate that CTFs associate with Ab42 to form heterooligomers, consistent with quasielastic light scattering data. We show that the presence of CTFs significantly reduces SASA in the N- terminal region of Ab42 compared to the same region in Ab42 oligomers formed in the absence of CTFs.We further explore folding and oligomer formation of the Arctic mutants, [E22G]Ab40 and [E22G]Ab42, associated with a familial form of AD. Our results demonstrate that the substitution E22G disrupts the folding structure and oligomerization pathways of both Arctic mutants and results in increased SASA at the N-terminus of the Arctic Ab40 mutant. These findings suggest that Ab oligomer neurotoxicity might be directly or indirectly associated with the degree of solvent exposure of the N-terminal region of Ab. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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