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Identification of key regions and residues controlling A? folding and assembly.


ABSTRACT: Amyloid ?-protein (A?) assembly is hypothesized to be a seminal neuropathologic event in Alzheimer's disease (AD). We used an unbiased D-amino acid substitution strategy to determine structure-assembly relationships of 76 different A?40 and A?42 peptides. We determined the effects of the substitutions on peptide oligomerization, secondary structure dynamics, fibril assembly dynamics, and fibril morphology. Our experiments revealed that the assembly of A?42 was more sensitive to chiral substitutions than was A?40 assembly. Substitutions at identical positions in the two peptides often, but not always, produced the same effects on assembly. Sites causing substantial effects in both A?40 and A?42 include His14, Gln15, Ala30, Ile31, Met35, and Val36. Sites whose effects were unique to A?40 include Lys16, Leu17, and Asn 27, whereas sites unique to A?42 include Phe20 and Ala21. These sites may be appropriate targets for therapeutic agents that inhibit or potentiate, respectively, these effects.

SUBMITTER: Hayden EY 

PROVIDER: S-EPMC5626695 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Identification of key regions and residues controlling Aβ folding and assembly.

Hayden Eric Y EY   Hoi Kimberly K KK   Lopez Jasmine J   Inayathullah Mohammed M   Condron Margaret M MM   Teplow David B DB  

Scientific reports 20171003 1


Amyloid β-protein (Aβ) assembly is hypothesized to be a seminal neuropathologic event in Alzheimer's disease (AD). We used an unbiased D-amino acid substitution strategy to determine structure-assembly relationships of 76 different Aβ40 and Aβ42 peptides. We determined the effects of the substitutions on peptide oligomerization, secondary structure dynamics, fibril assembly dynamics, and fibril morphology. Our experiments revealed that the assembly of Aβ42 was more sensitive to chiral substituti  ...[more]

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