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.
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
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
J. Biol. Chem.
Date: Oct. 18, 2002
PubMed ID: 12198112
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