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

    7 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

    Fingerprint

    Dive into the research topics of 'Specific mutations in presenilin 1 cause conformational changes in γ-secretase to modulate amyloid β trimming'. Together they form a unique fingerprint.

    Cite this