Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide

Using a coarse-grained model of the Aβ 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...

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Published in:Biophysical Journal
Main Authors: Fawzi, NL, Kohlstedt, KL, Okabe, Y, Head-Gordon, T
Format: Article in Journal/Newspaper
Language:English
Published: eScholarship, University of California 2008
Subjects:
Online Access:http://www.escholarship.org/uc/item/8qw2m08v
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spelling ftcdlib:qt8qw2m08v 2023-05-15T14:25:42+02:00 Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide Fawzi, NL Kohlstedt, KL Okabe, Y Head-Gordon, T 2007 - 2016 2008-03-15 application/pdf http://www.escholarship.org/uc/item/8qw2m08v english eng eScholarship, University of California qt8qw2m08v http://www.escholarship.org/uc/item/8qw2m08v public Fawzi, NL; Kohlstedt, KL; Okabe, Y; & Head-Gordon, T. (2008). Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide. Biophysical Journal, 94(6), 2007 - 2016. doi:10.1529/biophysj.107.121467. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/8qw2m08v article 2008 ftcdlib https://doi.org/10.1529/biophysj.107.121467 2018-11-09T23:51:57Z Using a coarse-grained model of the Aβ 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 Aβ 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. © 2008 by the Biophysical Society. Article in Journal/Newspaper Arctic Arctic University of California: eScholarship Arctic Biophysical Journal 94 6 2007 2016
institution Open Polar
collection University of California: eScholarship
op_collection_id ftcdlib
language English
description Using a coarse-grained model of the Aβ 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 Aβ 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. © 2008 by the Biophysical Society.
format Article in Journal/Newspaper
author Fawzi, NL
Kohlstedt, KL
Okabe, Y
Head-Gordon, T
spellingShingle Fawzi, NL
Kohlstedt, KL
Okabe, Y
Head-Gordon, T
Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide
author_facet Fawzi, NL
Kohlstedt, KL
Okabe, Y
Head-Gordon, T
author_sort Fawzi, NL
title Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide
title_short Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide
title_full Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide
title_fullStr Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide
title_full_unstemmed Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide
title_sort protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's aβ 1-40 peptide
publisher eScholarship, University of California
publishDate 2008
url http://www.escholarship.org/uc/item/8qw2m08v
op_coverage 2007 - 2016
geographic Arctic
geographic_facet Arctic
genre Arctic
Arctic
genre_facet Arctic
Arctic
op_source Fawzi, NL; Kohlstedt, KL; Okabe, Y; & Head-Gordon, T. (2008). Protofibril assemblies of the arctic, dutch, and flemish mutants of the alzheimer's Aβ 1-40 peptide. Biophysical Journal, 94(6), 2007 - 2016. doi:10.1529/biophysj.107.121467. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/8qw2m08v
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op_doi https://doi.org/10.1529/biophysj.107.121467
container_title Biophysical Journal
container_volume 94
container_issue 6
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