Sequential conformational changes in transmembrane domains of presenilin 1 in Aβ42 downregulation

Alzheimer disease (AD) is the most common neurodegenerative disease worldwide. AD is pathologically characterized by the deposition of senile plaques in the brain, which are composed of an amyloid-β peptide (Aβ) that is produced through the multistep cleavage of amyloid precursor protein (APP) by γ-secretase. γ-Secretase is a membrane protein complex, which includes its catalytic subunit presenilin 1 (PS1). However, much about the structural dynamics of this enzyme remain unclear. We have previously demonstrated that movements of the transmembrane domain (TMD) 1 and TMD3 of PS1 are strongly associated with decreased production of the Aβ peptide ending at the 42nd residue (i.e. Aβ42), which is the aggregation-prone, toxic species. However, the association between these movements as well as the sequence of these TMDs remains unclear. In this study, we raised the possibility that the vertical movement of TMD1 is a prerequisite for expansion of the catalytic cavity around TMD3 of PS1, resulting in reduced Aβ42 production. Our results shed light on the association between the conformational changes of TMDs and the regulation of γ-secretase activity.