Conformational Changes in Transmembrane Domain 4 of Presenilin 1 Are Associated with Altered Amyloid-β 42 Production.

γ-Secretase is an intramembrane-cleaving protease that produces amyloid-β peptide 42 (Aβ42), which is the toxic and aggregation-prone species of Aβ that causes Alzheimer's disease. Here, we used the substituted cysteine accessibility method to analyze the structure of transmembrane domains (TMDs) 4 and 5 of human presenilin 1 (PS1), a catalytic subunit of γ-secretase. We revealed that TMD4 and TMD5 face the intramembranous hydrophilic milieu together with TMD1, TMD6, TMD7, and TMD9 of PS1 to form the catalytic pore structure. Notably, we found a correlation in the distance between the cytosolic sides of TMD4/TMD7 and Aβ42 production levels, suggesting that allosteric conformational changes of the cytosolic side of TMD4 affect Aβ42-generating γ-secretase activity. Our results provide new insights into the relationship between the structure and activity of human PS1. SIGNIFICANCE STATEMENT: Modulation of γ-secretase activity to reduce toxic amyloid-β peptide species is one plausible therapeutic approaches for Alzheimer's disease. However, precise mechanistic information of γ-secretase still remains unclear. Here we identified the conformational changes in transmembrane domains of presenilin 1 that affect the proteolytic activity of the γ-secretase. Our results highlight the importance of understanding the structural dynamics of presenilin 1 in drug development against Alzheimer's disease.