Conformational changes in transmembrane domain 4 of presenilin 1 are associated with altered amyloid-β 42 production

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Abstract

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.

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Tominaga, A., Cai, T., Takagi-Niidome, S., Iwatsubo, T., & Tomita, T. (2016). Conformational changes in transmembrane domain 4 of presenilin 1 are associated with altered amyloid-β 42 production. Journal of Neuroscience, 36(4), 1362–1372. https://doi.org/10.1523/JNEUROSCI.5090-14.2016

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