G37V mutation of Aβ42 induces a nontoxic ellipse-like aggregate: An in vitro and in silico study

Neurochemistry International
Tran Thi Minh ThuYi-Cheng Chen

Abstract

The glycine zipper motif at the C-terminus of the β-amyloid (Aβ) peptide have been shown to strongly influence the formation of neurotoxic aggregates. A previous study showed that the G37L mutation dramatically reduces the Aβ toxicity in vivo and in vitro. However, the primary cause and mechanism of the glycine zipper motif on Aβ properties remain unknown. To gain molecular insights into the impact of glycine zipper on Aβ properties, we substituted the residue 37 of Glycine by Valine and studied the structural and biochemical properties of G37V mutation, Aβ42(37V), by using in vitro and in silico approaches. Unlike G37L mutation, the G37V mutation reduced toxicity substantially but did not significantly accelerate the aggregation rate or change the content of secondary structures. Further TEM analyses showed that the G37V mutation formed an ellipse-like aggregate rather than a network-like fibril as wild type or G37L mutation of Aβ42 form. This different aggregation morphology may be highly linked with the reduction of toxicity. To gain the insight for the different properties of Aβ42(37V), we studied the structure of Aβ42 and G37V mutation using the replica exchange molecular dynamics simulation. Our results demonstrate that a...Continue Reading

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