Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.

ABSTRACT: The γ-secretase complex catalyzes the intramembrane cleavage of C99, a carboxy-terminal fragment of the amyloid precursor protein. Two paralogs of its catalytic subunit presenilin (PS1 and PS2) are expressed which are autocatalytically cleaved into an N-terminal and a C-terminal fragment during maturation of γ-secretase. In this study, we compared the efficiency and specificity of C99 cleavage by PS1- and PS2-containing γ-secretases. Mass spectrometric analysis of cleavage products obtained in cell-free and cell-based assays revealed that the previously described lower amyloid-β (Aβ)38 generation by PS2 is accompanied by a reciprocal increase in Aβ37 production. We further found PS1 and PS2 to show different preferences in the choice of the initial cleavage site of C99. However, the differ

SUBMITTER: Schmidt FC 

PROVIDER: S-EPMC10164903 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature