Activation of γ-secretase trimming activity by topological changes of transmembrane domain 1 of presenilin 1

Abstract

γ-Secretase is an intramembrane cleaving protease that is responsible for the generation of amyloid-β peptides, which are linked to the pathogenesis of Alzheimer disease. Recently, γ-secretase modulators (GSMs) have been shown to specifically decrease production of the aggregation-prone and toxic longer Aβ species, and concomitantly increase the levels of shorter Aβ. We previously found that phenylimidazole-type GSMs bind to presenilin 1 (PS1), the catalytic subunit of the γ-secretase, and allosterically modulate γ-secretase activity. However, the precise conformational alterations in PS1 remained unclear. Here we mapped the amino acid residues in PS1 that is crucial for the binding and pharmacological actions of E2012, a phenylimidazole-type GSM, using photoaffinity labeling and the substituted cysteine accessibility method. We also demonstrated that a piston-like vertical motion of transmembrane domain (TMD) 1 occurs during modulation of Aβ production. Taking these results together, we propose a model for the molecular mechanism of phenylimidazole-type GSMs, in which the trimming activity of γ-secretase is modulated by the position of the TMD1 of PS1 in the lipid bilayer.