Recognition of the amyloid precursor protein by human γ-secretase

Science. 2019 Feb 15;363(6428):eaaw0930. doi: 10.1126/science.aaw0930. Epub 2019 Jan 10.


Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human γ-secretase in complex with a transmembrane (TM) APP fragment at 2.6-angstrom resolution. The TM helix of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of γ-secretase). A hybrid β sheet, which is formed by a β strand from APP and two β strands from PS1, guides γ-secretase to the scissile peptide bond of APP between its TM and β strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of γ-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloid beta-Protein Precursor / chemistry*
  • Catalytic Domain*
  • Cryoelectron Microscopy
  • Humans
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Proteolysis*
  • Receptors, Notch / chemistry


  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Receptors, Notch
  • Amyloid Precursor Protein Secretases