Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy

J Biol Chem. 2011 Jun 17;286(24):21440-9. doi: 10.1074/jbc.M110.193326. Epub 2011 Mar 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / chemistry
  • Catalysis
  • Catalytic Domain
  • Cryoelectron Microscopy / methods
  • Dimerization
  • Humans
  • Membrane Proteins / chemistry
  • Microscopy, Electron / methods*
  • Peptides / chemistry
  • Protein Binding
  • Protein Conformation
  • Signal Transduction


  • Amyloid beta-Peptides
  • Membrane Proteins
  • PSENEN protein, human
  • Peptides
  • Amyloid Precursor Protein Secretases