Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide.
Using a coarse-grained model of the Abeta peptide, we analyze the Arctic (E22G), Dutch (E22Q), and Flemish (A21G) familial Alzheimer's disease (FAD) mutants for any changes in the stability of amyloid assemblies with respect to the wild-type (WT) sequence. Based on a structural reference state...
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ftcdlib:oai:escholarship.org/ark:/13030/qt8qw2m08v 2023-05-15T14:51:54+02:00 Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide. Fawzi, Nicolas Lux Kohlstedt, Kevin L Okabe, Yuka Head-Gordon, Teresa 2007 - 2016 2008-03-01 application/pdf https://escholarship.org/uc/item/8qw2m08v unknown eScholarship, University of California qt8qw2m08v https://escholarship.org/uc/item/8qw2m08v public Biophysical journal, vol 94, iss 6 Alzheimer Disease Genetic Predisposition to Disease Peptides Peptide Fragments Proteins Chromatography Magnetic Resonance Spectroscopy Models Statistical Molecular Conformation Protein Conformation Protein Structure Secondary Mutation Thermodynamics Arctic Regions Netherlands Amyloid beta-Peptides Biophysics Physical Sciences Chemical Sciences Biological Sciences article 2008 ftcdlib 2021-01-24T17:37:04Z Using a coarse-grained model of the Abeta peptide, we analyze the Arctic (E22G), Dutch (E22Q), and Flemish (A21G) familial Alzheimer's disease (FAD) mutants for any changes in the stability of amyloid assemblies with respect to the wild-type (WT) sequence. Based on a structural reference state of two protofilaments aligned to create the "agitated" protofibril as determined by solid-state NMR, we determine free energy trends for Abeta assemblies for the WT and FAD familial sequences. We find that the structural characteristics and oligomer size of the critical nucleus vary dramatically among the hereditary mutants. The Arctic mutant's disorder in the turn region introduces new stabilizing interactions that better align the two protofilaments, yielding a well-defined protofibril axis at relatively small oligomer sizes with respect to WT. By contrast, the critical nucleus for the Flemish mutant is beyond the 20 chains characterized in this study, thereby showing a strong shift in the equilibrium toward monomers with respect to larger protofibril assemblies. The Dutch mutant forms more ordered protofilaments than WT, but exhibits greater disorder in protofibril structure that includes an alternative polymorph of the WT fibril. An important conclusion of this work is that the Dutch mutant does not support the agitated protofibril assembly. We discuss the implications of the structural ensembles and free energy profiles for the FAD mutants in regards to interpretation of the kinetics of fibril assembly using chromatography and dye-binding experiments. Article in Journal/Newspaper Arctic University of California: eScholarship Arctic |
institution |
Open Polar |
collection |
University of California: eScholarship |
op_collection_id |
ftcdlib |
language |
unknown |
topic |
Alzheimer Disease Genetic Predisposition to Disease Peptides Peptide Fragments Proteins Chromatography Magnetic Resonance Spectroscopy Models Statistical Molecular Conformation Protein Conformation Protein Structure Secondary Mutation Thermodynamics Arctic Regions Netherlands Amyloid beta-Peptides Biophysics Physical Sciences Chemical Sciences Biological Sciences |
spellingShingle |
Alzheimer Disease Genetic Predisposition to Disease Peptides Peptide Fragments Proteins Chromatography Magnetic Resonance Spectroscopy Models Statistical Molecular Conformation Protein Conformation Protein Structure Secondary Mutation Thermodynamics Arctic Regions Netherlands Amyloid beta-Peptides Biophysics Physical Sciences Chemical Sciences Biological Sciences Fawzi, Nicolas Lux Kohlstedt, Kevin L Okabe, Yuka Head-Gordon, Teresa Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide. |
topic_facet |
Alzheimer Disease Genetic Predisposition to Disease Peptides Peptide Fragments Proteins Chromatography Magnetic Resonance Spectroscopy Models Statistical Molecular Conformation Protein Conformation Protein Structure Secondary Mutation Thermodynamics Arctic Regions Netherlands Amyloid beta-Peptides Biophysics Physical Sciences Chemical Sciences Biological Sciences |
description |
Using a coarse-grained model of the Abeta peptide, we analyze the Arctic (E22G), Dutch (E22Q), and Flemish (A21G) familial Alzheimer's disease (FAD) mutants for any changes in the stability of amyloid assemblies with respect to the wild-type (WT) sequence. Based on a structural reference state of two protofilaments aligned to create the "agitated" protofibril as determined by solid-state NMR, we determine free energy trends for Abeta assemblies for the WT and FAD familial sequences. We find that the structural characteristics and oligomer size of the critical nucleus vary dramatically among the hereditary mutants. The Arctic mutant's disorder in the turn region introduces new stabilizing interactions that better align the two protofilaments, yielding a well-defined protofibril axis at relatively small oligomer sizes with respect to WT. By contrast, the critical nucleus for the Flemish mutant is beyond the 20 chains characterized in this study, thereby showing a strong shift in the equilibrium toward monomers with respect to larger protofibril assemblies. The Dutch mutant forms more ordered protofilaments than WT, but exhibits greater disorder in protofibril structure that includes an alternative polymorph of the WT fibril. An important conclusion of this work is that the Dutch mutant does not support the agitated protofibril assembly. We discuss the implications of the structural ensembles and free energy profiles for the FAD mutants in regards to interpretation of the kinetics of fibril assembly using chromatography and dye-binding experiments. |
format |
Article in Journal/Newspaper |
author |
Fawzi, Nicolas Lux Kohlstedt, Kevin L Okabe, Yuka Head-Gordon, Teresa |
author_facet |
Fawzi, Nicolas Lux Kohlstedt, Kevin L Okabe, Yuka Head-Gordon, Teresa |
author_sort |
Fawzi, Nicolas Lux |
title |
Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide. |
title_short |
Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide. |
title_full |
Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide. |
title_fullStr |
Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide. |
title_full_unstemmed |
Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide. |
title_sort |
protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's abeta1-40 peptide. |
publisher |
eScholarship, University of California |
publishDate |
2008 |
url |
https://escholarship.org/uc/item/8qw2m08v |
op_coverage |
2007 - 2016 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Biophysical journal, vol 94, iss 6 |
op_relation |
qt8qw2m08v https://escholarship.org/uc/item/8qw2m08v |
op_rights |
public |
_version_ |
1766323049608511488 |