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Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch.

Presenilin and nicastrin are essential components of the gamma-secretase complex that is required for the intramembrane proteolysis of an increasing number of membrane proteins including the amyloid-beta precursor protein (APP) and Notch. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian APH-1 (mAPH-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous mAPH-1 using small interfering RNAs results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (APP carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of APP and Notch). These data indicate that mAPH-1 is probably a functional component of the gamma-secretase complex required for the intramembrane proteolysis of APP and Notch.

Pubmed ID: 12297508

Authors

  • Lee SF
  • Shah S
  • Li H
  • Yu C
  • Han W
  • Yu G

Journal

The Journal of biological chemistry

Publication Data

November 22, 2002

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • Brain
  • Cell Line
  • Dimerization
  • Endopeptidases
  • Genes, Reporter
  • Humans
  • Membrane Glycoproteins
  • Membrane Proteins
  • Molecular Sequence Data
  • Oligonucleotides
  • Peptide Hydrolases
  • Presenilin-1
  • Protein Binding
  • RNA, Small Interfering
  • Rats
  • Receptors, Notch
  • Recombinant Fusion Proteins
  • Sequence Alignment
  • Trans-Activators