Specific mutations in presenilin 1 cause conformational changes in γ-secretase to modulate amyloid β trimming

So Imai, Tetsuo Cai, Chika Yoshida, Taisuke Tomita, Eugene Futai

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

c-Secretase generates amyloid beta peptides (Ab) from amyloid precursor protein through multistep cleavages, such as endoproteolysis (e-cleavage) and trimming (c-cleavage). Familial Alzheimer's disease (FAD) mutations within the catalytic subunit protein of presenilin 1 (PS1) decrease c-cleavage, resulting in the generation of toxic, long Abs. Reducing long Ab levels has been proposed as an AD therapeutic strategy. Previously, we identified PS1 mutations that are active in the absence of nicastrin (NCT) using a yeast c-secretase assay. Here, we analysed these PS1 mutations in the presence of NCT, and found that they were constitutively active in yeast. One triple, 13 double, and 5 single mutants enhanced e-cleavage activity up to 2.7-fold. Furthermore, L241I, F411Y, S438P and F441L mutations modulated trimming activities to produce more short-Ab in yeast microsomes. When introduced in mouse embryonic fibroblasts, these mutations possessed similar or reduced e-cleavage activity. However, two mutations, L241I and S438P, modulated trimming activities and changed the conformation of transmembrane domain 1, the substrate recognition site. These mutants had the opposite modulatory effects of FAD mutations and produced more short Abs and fewer long Abs. Our results provide insights into the relationship between PS1 conformational changes and c-secretase activities.

Original languageEnglish
Pages (from-to)37-46
Number of pages10
JournalJournal of biochemistry
Volume165
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1

Keywords

  • Alzheimer's disease
  • Saccharomyces cerevisiae
  • amyloid beta (Ab)
  • csecretase
  • intramembrane proteolysis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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