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.
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, Precipitin Tests, Presenilin-1, Presenilin-2, Protein Binding, Sequence Homology, Amino Acid, Temperature, Transfection, Triiodobenzoic Acids
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, Precipitin Tests, Presenilin-1, Presenilin-2, Protein Binding, Sequence Homology, Amino Acid, Temperature, Transfection, Triiodobenzoic Acids
J. Biol. Chem.
Date: Feb. 28, 2003
PubMed ID: 12471034
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