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APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes.

APH-1 and PEN-2 genes modulate the function of nicastrin and the presenilins in Caenorhabditis elegans. Preliminary studies in transfected mammalian cells overexpressing tagged APH-1 proteins suggest that this genetic interaction is mediated by a direct physical interaction. Using the APH-1 protein encoded on human chromosome 1 (APH-1(1)L; also known as APH-1a) as an archetype, we report here that endogenous forms of APH-1 are predominantly expressed in intracellular membrane compartments, including the endoplasmic reticulum and cis-Golgi. APH-1 proteins directly interact with immature and mature forms of the presenilins and nicastrin within high molecular weight complexes that display gamma- and epsilon-secretase activity. Indeed APH-1 proteins can bind to the nicastrin delta312-369 loss of function mutant, which does not undergo glycosylation maturation and is not trafficking beyond the endoplasmic reticulum. The levels of expression of endogenous APH-1(1)L can be suppressed by overexpression of any other members of the APH-1 family, suggesting that their abundance is coordinately regulated. Finally, although the absence of APH-1 destabilizes the presenilins, in contrast to nicastrin and PEN-2, APH-1 itself is only modestly destabilized in cells lacking functional expression of presenilin 1 or presenilin 2. Taken together, our data suggest that APH-1 proteins, and APH-1(1) in particular, may have a role in the initial assembly and maturation of presenilin.nicastrin complexes.

Pubmed ID: 12471034

Authors

  • Gu Y
  • Chen F
  • Sanjo N
  • Kawarai T
  • Hasegawa H
  • Duthie M
  • Li W
  • Ruan X
  • Luthra A
  • Mount HT
  • Tandon A
  • Fraser PE
  • St George-Hyslop P

Journal

The Journal of biological chemistry

Publication Data

February 28, 2003

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Blotting, Western
  • Brain
  • Catalysis
  • Cell Line
  • Centrifugation
  • DNA, Complementary
  • Endoplasmic Reticulum
  • Glycosylation
  • Golgi Apparatus
  • Humans
  • Immunohistochemistry
  • Membrane Glycoproteins
  • Membrane Proteins
  • Molecular Sequence Data
  • Peptide Hydrolases
  • Precipitin Tests
  • Presenilin-1
  • Presenilin-2
  • Protein Binding
  • Sequence Homology, Amino Acid
  • Temperature
  • Transfection
  • Triiodobenzoic Acids