Conformational dynamics of transmembrane domain 3 of presenilin 1 is associated with the trimming activity of γ-Secretase

Abstract

γ-Secretase is an intramembrane-cleaving protease that generates the toxic species of the amyloid-α peptide (Aα) that is responsible for the pathology of Alzheimer disease. The catalytic subunit ofγ-secretase is presenilin 1 (PS1), which is a polytopic membrane protein with a hydrophilic catalytic pore. The length of the C terminus of Aα is proteolytically determined by its processive trimming by γ-secretase, although the precise mechanism still remains largely unknown. Here, we identified that transmembrane domain (TMD) 3 of human PS1 is involved in the formation of the intramembranous hydrophilic pore. Notably, the water accessibility of TMD3 was greatly altered by point mutations and compounds, which modify γ-secretase activity. The changes in the water accessibility of TMD3 was also correlated with Aα42 production. Moreover, crosslinking between TMD3 and TMD7 resulted in a loss of sensitivity to a γ-secretase modulator that reduces Aα42 production. Therefore, our findings indicate that the conformational dynamics of TMD3 is a prerequisite for regulation of the Aα trimming activity of γ-secretase.