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Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.

gamma-Secretase catalyzes the intramembrane proteolysis of Notch, beta-amyloid precursor protein, and other substrates as part of a new signaling paradigm and as a key step in the pathogenesis of Alzheimer's disease. This unusual protease has eluded identification, though evidence suggests that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. The formation of presenilin heterodimers from the holoprotein is tightly gated by unknown limiting cellular factors. Here we show that Aph-1 and Pen-2, two recently identified membrane proteins genetically linked to gamma-secretase, associate directly with presenilin and nicastrin in the active protease complex. Coexpression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced gamma-secretase activity. These findings suggest that the four membrane proteins comprise the limiting components of gamma-secretase and coassemble to form the active enzyme in mammalian cells.

Pubmed ID: 12740439


  • Kimberly WT
  • LaVoie MJ
  • Ostaszewski BL
  • Ye W
  • Wolfe MS
  • Selkoe DJ


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 27, 2003

Associated Grants


Mesh Terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Caenorhabditis elegans Proteins
  • Cricetinae
  • Cricetulus
  • Endopeptidases
  • Homeodomain Proteins
  • Membrane Glycoproteins
  • Membrane Proteins