title: Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy.
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.
authors: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors: Fabiana
authors: F
authors: Renzi
authors: Xulun
authors: X
authors: Zhang
authors: William J
authors: WJ
authors: Rice
authors: Celia
authors: C
authors: Torres-Arancivia
authors: Yacob
authors: Y
authors: Gomez-Llorente
authors: Ruben
authors: R
authors: Diaz
authors: Kwangwook
authors: K
authors: Ahn
authors: Chunjiang
authors: C
authors: Yu
authors: Yue-Ming
authors: YM
authors: Li
authors: Sangram S
authors: SS
authors: Sisodia
authors: Iban
authors: I
authors: Ubarretxena-Belandia
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry; D002384:Catalysis; D020134:Catalytic Domain; D020285:Cryoelectron Microscopy / Q000379:methods; D019281:Dimerization; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry; D008854:Microscopy, Electron / Q000379:methods*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C469349:PSENEN protein, human; D010455:Peptides; D053829:Amyloid Precursor Protein Secretases