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PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin.

The Alzheimer disease-associated presenilin (PS) proteins apparently provide the active site of gamma-secretase, an unusual intramembrane-cleaving aspartyl protease. PSs principally occur as high molecular weight protein complexes that contain nicastrin (Nct) and additional so far unidentified components. Recently, PEN-2 has been implicated in gamma-secretase function. Here we identify PEN-2 as a critical component of PS1/gamma-secretase and PS2/gamma-secretase complexes. Strikingly, in the absence of PS1 and PS1/PS2, PEN-2 levels are strongly reduced. Similarly, PEN-2 levels are reduced upon RNA interference-mediated down-regulation of Nct. On the other side, down-regulation of PEN-2 by RNA interference is associated with reduced PS levels, impaired Nct maturation, and deficient gamma-secretase complex formation. We conclude that PEN-2 is an integral gamma-secretase complex component and that gamma-secretase complex components are expressed in a coordinated manner.

Pubmed ID: 12198112

Authors

  • Steiner H
  • Winkler E
  • Edbauer D
  • Prokop S
  • Basset G
  • Yamasaki A
  • Kostka M
  • Haass C

Journal

The Journal of biological chemistry

Publication Data

October 18, 2002

Associated Grants

None

Mesh Terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Cell Line
  • DNA, Complementary
  • Down-Regulation
  • Electrophoresis, Polyacrylamide Gel
  • Endopeptidases
  • Epitopes
  • Humans
  • Membrane Glycoproteins
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Precipitin Tests
  • Presenilin-1
  • Presenilin-2
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA