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 beta-protein (Abeta) is investigate...
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2008
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ftcdlib:oai:escholarship.org:ark:/13030/qt42c6d3jx 2023-09-05T13:17:38+02:00 Effects of Familial Alzheimer’s Disease Mutations on the Folding Nucleation of the Amyloid β-Protein Krone, Mary Griffin Baumketner, Andrij Bernstein, Summer L Wyttenbach, Thomas Lazo, Noel D Teplow, David B Bowers, Michael T Shea, Joan-Emma 221 - 228 2008-08-01 application/pdf https://escholarship.org/uc/item/42c6d3jx unknown eScholarship, University of California qt42c6d3jx https://escholarship.org/uc/item/42c6d3jx public Journal of Molecular Biology, vol 381, iss 1 Brain Disorders Alzheimer's Disease Neurosciences Acquired Cognitive Impairment Aging Neurodegenerative Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Dementia Aetiology 2.1 Biological and endogenous factors Neurological Alzheimer Disease Amyloid beta-Peptides Humans Models Molecular Mutation Protein Folding Protein Structure Tertiary amyloid beta-protein molecular dynamics simulations replica exchange familial Alzheimer's disease Medicinal and Biomolecular Chemistry Biochemistry and Cell Biology Microbiology Biochemistry & Molecular Biology article 2008 ftcdlib 2023-08-21T18:04:42Z 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 beta-protein (Abeta) 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 Abeta. 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 Abeta. Enhanced aggregation in Abeta 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 Abeta. 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 Abeta folding and subsequent aggregation. Our simulations suggest that the mechanisms by which E22 and D23 mutations affect the folding and aggregation of Abeta are fundamentally different. Article in Journal/Newspaper Arctic University of California: eScholarship Arctic |
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University of California: eScholarship |
op_collection_id |
ftcdlib |
language |
unknown |
topic |
Brain Disorders Alzheimer's Disease Neurosciences Acquired Cognitive Impairment Aging Neurodegenerative Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Dementia Aetiology 2.1 Biological and endogenous factors Neurological Alzheimer Disease Amyloid beta-Peptides Humans Models Molecular Mutation Protein Folding Protein Structure Tertiary amyloid beta-protein molecular dynamics simulations replica exchange familial Alzheimer's disease Medicinal and Biomolecular Chemistry Biochemistry and Cell Biology Microbiology Biochemistry & Molecular Biology |
spellingShingle |
Brain Disorders Alzheimer's Disease Neurosciences Acquired Cognitive Impairment Aging Neurodegenerative Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Dementia Aetiology 2.1 Biological and endogenous factors Neurological Alzheimer Disease Amyloid beta-Peptides Humans Models Molecular Mutation Protein Folding Protein Structure Tertiary amyloid beta-protein molecular dynamics simulations replica exchange familial Alzheimer's disease Medicinal and Biomolecular Chemistry Biochemistry and Cell Biology Microbiology Biochemistry & Molecular Biology Krone, Mary Griffin Baumketner, Andrij Bernstein, Summer L Wyttenbach, Thomas Lazo, Noel D Teplow, David B Bowers, Michael T Shea, Joan-Emma Effects of Familial Alzheimer’s Disease Mutations on the Folding Nucleation of the Amyloid β-Protein |
topic_facet |
Brain Disorders Alzheimer's Disease Neurosciences Acquired Cognitive Impairment Aging Neurodegenerative Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Dementia Aetiology 2.1 Biological and endogenous factors Neurological Alzheimer Disease Amyloid beta-Peptides Humans Models Molecular Mutation Protein Folding Protein Structure Tertiary amyloid beta-protein molecular dynamics simulations replica exchange familial Alzheimer's disease Medicinal and Biomolecular Chemistry Biochemistry and Cell Biology Microbiology Biochemistry & Molecular Biology |
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 beta-protein (Abeta) 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 Abeta. 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 Abeta. Enhanced aggregation in Abeta 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 Abeta. 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 Abeta folding and subsequent aggregation. Our simulations suggest that the mechanisms by which E22 and D23 mutations affect the folding and aggregation of Abeta are fundamentally different. |
format |
Article in Journal/Newspaper |
author |
Krone, Mary Griffin Baumketner, Andrij Bernstein, Summer L Wyttenbach, Thomas Lazo, Noel D Teplow, David B Bowers, Michael T Shea, Joan-Emma |
author_facet |
Krone, Mary Griffin Baumketner, Andrij Bernstein, Summer L Wyttenbach, Thomas Lazo, Noel D Teplow, David B Bowers, Michael T Shea, Joan-Emma |
author_sort |
Krone, Mary Griffin |
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 |
https://escholarship.org/uc/item/42c6d3jx |
op_coverage |
221 - 228 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Journal of Molecular Biology, vol 381, iss 1 |
op_relation |
qt42c6d3jx https://escholarship.org/uc/item/42c6d3jx |
op_rights |
public |
_version_ |
1776198739624460288 |