Elucidating the Molecular Determinants of Aβ Aggregation with Deep Mutational Scanning.

ABSTRACT: Despite the importance of Aβ aggregation in Alzheimer's disease etiology, our understanding of the sequence determinants of aggregation is sparse and largely derived from in vitro studies. For example, in vitro proline and alanine scanning mutagenesis of Aβ₄₀ proposed core regions important for aggregation. However, we lack even this limited mutagenesis data for the more disease-relevant Aβ₄₂ Thus, to better understand the molecular determinants of Aβ₄₂ aggregation in a cell-based system, we combined a yeast DHFR aggregation assay with deep mutational scanning. We measured the effect of 791 of the 798 possible single amino acid substitutions on the aggregation propensity of Aβ₄₂ We found that ∼75% of substitutions, largely to hydrop

SUBMITTER: Gray VE 

PROVIDER: S-EPMC6829127 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature