Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein
The effect of single amino acid substitutions associated with the Italian (E22K), Arctic (E22G), Dutch (E22Q) and Iowa (D23N) familial forms of Alzheimer's disease and cerebral amyloid angiopathy on the structure of the 21-30 fragment of the Alzheimer amyloid β-protein (Aβ) is investigated by r...
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ftcdlib:qt42c6d3jx 2023-05-15T15:08:52+02:00 Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein Krone, MG Baumketner, A Bernstein, SL Wyttenbach, T Lazo, ND Teplow, DB Bowers, MT Shea, JE 221 - 228 2008-08-01 application/pdf http://www.escholarship.org/uc/item/42c6d3jx english eng eScholarship, University of California qt42c6d3jx http://www.escholarship.org/uc/item/42c6d3jx public Krone, MG; Baumketner, A; Bernstein, SL; Wyttenbach, T; Lazo, ND; Teplow, DB; et al.(2008). Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein. Journal of Molecular Biology, 381(1), 221 - 228. doi:10.1016/j.jmb.2008.05.069. UCLA: Retrieved from: http://www.escholarship.org/uc/item/42c6d3jx article 2008 ftcdlib https://doi.org/10.1016/j.jmb.2008.05.069 2017-10-13T22:51:29Z The effect of single amino acid substitutions associated with the Italian (E22K), Arctic (E22G), Dutch (E22Q) and Iowa (D23N) familial forms of Alzheimer's disease and cerebral amyloid angiopathy on the structure of the 21-30 fragment of the Alzheimer amyloid β-protein (Aβ) is investigated by replica-exchange molecular dynamics simulations. The 21-30 segment has been shown in our earlier work to adopt a bend structure in solution that may serve as the folding nucleation site for Aβ. Our simulations reveal that the 24-28 bend motif is retained in all E22 mutants, suggesting that mutations involving residue E22 may not affect the structure of the folding nucleation site of Aβ. Enhanced aggregation in Aβ with familial Alzheimer's disease substitutions may result from the depletion of the E22-K28 salt bridge, which destabilizes the bend structure. Alternately, the E22 mutations may affect longer-range interactions outside the 21-30 segment that can impact the aggregation of Aβ. Substituting at residue D23, on the other hand, leads to the formation of a turn rather than a bend motif, implying that in contrast to E22 mutants, the D23N mutant may affect monomer Aβ folding and subsequent aggregation. Our simulations suggest that the mechanisms by which E22 and D23 mutations affect the folding and aggregation of Aβ are fundamentally different. © 2008 Elsevier Ltd. All rights reserved. Article in Journal/Newspaper Arctic University of California: eScholarship Arctic Journal of Molecular Biology 381 1 221 228 |
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University of California: eScholarship |
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English |
description |
The effect of single amino acid substitutions associated with the Italian (E22K), Arctic (E22G), Dutch (E22Q) and Iowa (D23N) familial forms of Alzheimer's disease and cerebral amyloid angiopathy on the structure of the 21-30 fragment of the Alzheimer amyloid β-protein (Aβ) is investigated by replica-exchange molecular dynamics simulations. The 21-30 segment has been shown in our earlier work to adopt a bend structure in solution that may serve as the folding nucleation site for Aβ. Our simulations reveal that the 24-28 bend motif is retained in all E22 mutants, suggesting that mutations involving residue E22 may not affect the structure of the folding nucleation site of Aβ. Enhanced aggregation in Aβ with familial Alzheimer's disease substitutions may result from the depletion of the E22-K28 salt bridge, which destabilizes the bend structure. Alternately, the E22 mutations may affect longer-range interactions outside the 21-30 segment that can impact the aggregation of Aβ. Substituting at residue D23, on the other hand, leads to the formation of a turn rather than a bend motif, implying that in contrast to E22 mutants, the D23N mutant may affect monomer Aβ folding and subsequent aggregation. Our simulations suggest that the mechanisms by which E22 and D23 mutations affect the folding and aggregation of Aβ are fundamentally different. © 2008 Elsevier Ltd. All rights reserved. |
format |
Article in Journal/Newspaper |
author |
Krone, MG Baumketner, A Bernstein, SL Wyttenbach, T Lazo, ND Teplow, DB Bowers, MT Shea, JE |
spellingShingle |
Krone, MG Baumketner, A Bernstein, SL Wyttenbach, T Lazo, ND Teplow, DB Bowers, MT Shea, JE Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein |
author_facet |
Krone, MG Baumketner, A Bernstein, SL Wyttenbach, T Lazo, ND Teplow, DB Bowers, MT Shea, JE |
author_sort |
Krone, MG |
title |
Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein |
title_short |
Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein |
title_full |
Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein |
title_fullStr |
Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein |
title_full_unstemmed |
Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein |
title_sort |
effects of familial alzheimer's disease mutations on the folding nucleation of the amyloid β-protein |
publisher |
eScholarship, University of California |
publishDate |
2008 |
url |
http://www.escholarship.org/uc/item/42c6d3jx |
op_coverage |
221 - 228 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Krone, MG; Baumketner, A; Bernstein, SL; Wyttenbach, T; Lazo, ND; Teplow, DB; et al.(2008). Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein. Journal of Molecular Biology, 381(1), 221 - 228. doi:10.1016/j.jmb.2008.05.069. UCLA: Retrieved from: http://www.escholarship.org/uc/item/42c6d3jx |
op_relation |
qt42c6d3jx http://www.escholarship.org/uc/item/42c6d3jx |
op_rights |
public |
op_doi |
https://doi.org/10.1016/j.jmb.2008.05.069 |
container_title |
Journal of Molecular Biology |
container_volume |
381 |
container_issue |
1 |
container_start_page |
221 |
op_container_end_page |
228 |
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1766340142382972928 |