Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase.

γ-Secretase is an intramembrane-cleaving protease that generates the toxic species of the amyloid-β peptide (Aβ) that is responsible for the pathology of Alzheimer disease. The catalytic subunit of γ-secretase is presenilin 1 (PS1), which is a polytopic membrane protein with a hydrophilic catalytic pore. The length of the C terminus of Aβ 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 Aβ42 production. Moreover, crosslinking between TMD3 and TMD7 resulted in a loss of sensitivity to a γ-secretase modulator that reduces Aβ42 production. Therefore, our findings indicate that the conformational dynamics of TMD3 is a prerequisite for regulation of the Aβ trimming activity of γ-secretase.SIGNIFICANCE STATEMENT Modulation of γ-secretase activity to reduce the level of toxic amyloid-β species is thought to be a therapeutic strategy for Alzheimer disease. However, the detailed mechanism of the regulation of amyloid-β production, as well as the structure-and-activity relationship of γ-secretase remains unclear. Here we identified that the water accessibility around transmembrane domain 3 in presenilin 1 was increased along with a reduction in toxic amyloid-β production. Our findings demonstrate how the structure of presenilin 1 dynamically changes during amyloid-β production, and provides insights toward the development of treatments against Alzheimer disease.