Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy |
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Authors: | Renzi Fabiana Zhang Xulun Rice William J Torres-Arancivia Celia Gomez-Llorente Yacob Diaz Ruben Ahn Kwangwook Yu Chunjiang Li Yue-Ming Sisodia Sangram S Ubarretxena-Belandia Iban |
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Institution: | Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York 10029, USA. |
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Abstract: | The γ-secretase membrane protein complex is responsible for proteolytic maturation of signaling precursors and catalyzes the final step in the production of the amyloid β-peptides implicated in the pathogenesis of Alzheimer disease. The incorporation of PEN-2 (presenilin enhancer 2) into a pre-activation intermediate, composed of the catalytic subunit presenilin and the accessory proteins APH-1 (anterior pharynx-defective 1) and nicastrin, triggers the endoproteolysis of presenilin and results in an active tetrameric γ-secretase. We have determined the three-dimensional reconstruction of a mature and catalytically active γ-secretase using single-particle cryo-electron microscopy. γ-Secretase has a cup-like shape with a lateral belt of ∼40–50 Å in height that encloses a water-accessible internal chamber. Active site labeling with a gold-coupled transition state analog inhibitor suggested that the γ-secretase active site faces this chamber. Comparison with the structure of a trimeric pre-activation intermediate suggested that the incorporation of PEN-2 might contribute to the maturation of the active site architecture. |
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Keywords: | Aspartic Protease Electron Microscopy (EM) Intramembrane Proteolysis Membrane Proteins Secretases |
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