Aph-1 interacts at the cell surface with proteins in the active gamma-secretase complex and membrane-tethered Notch

J Neurochem. 2005 Mar;92(5):1010-20. doi: 10.1111/j.1471-4159.2004.02926.x.


The activity of the gamma-secretase complex is critical for the processing of a number of transmembrane proteins, including Notch. Functional gamma-secretase activity can be reconstituted from four proteins--presenilin, nicastrin, Pen-2 and Aph-1--but the role of the individual proteins remains unclear. In this report we describe the cellular localization and protein interactions of Aph-1, with particular regard to Notch receptor processing. We found that Aph-1 is present at the cell surface, where it interacts with Pen-2, the mature forms of presenilin and nicastrin, and full-length Notch. Aph-1 also interacts with a truncated form of Notch, which is a direct substrate for gamma-secretase, but not with the Notch intracellular domain. Immunoprecipitation data for Notch and Aph-1 showed that the Notch-containing gamma-secretase complexes most likely form a small subset of the total number of gamma-secretase complexes. In conclusion, these data demonstrate that Aph-1 is present at the cell surface, presumably in active gamma-secretase complexes, and interacts with the Notch receptor, both before and after ligand activation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Autoantigens
  • Blotting, Western / methods
  • Cell Line
  • Cell Membrane / metabolism*
  • Endopeptidases / metabolism*
  • Golgi Apparatus / metabolism
  • Hemagglutinins / metabolism
  • Humans
  • Immunohistochemistry / methods
  • Immunoprecipitation / methods
  • Indoles / metabolism
  • Macromolecular Substances / metabolism
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / metabolism*
  • Peptide Fragments / metabolism
  • Peptide Hydrolases
  • Presenilin-1
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptors, Notch
  • Transfection / methods


  • Autoantigens
  • Golgin subfamily A member 2
  • Hemagglutinins
  • Indoles
  • MYC protein, human
  • Macromolecular Substances
  • Membrane Glycoproteins
  • Membrane Proteins
  • PSEN1 protein, human
  • PSENEN protein, human
  • Peptide Fragments
  • Presenilin-1
  • Proto-Oncogene Proteins c-myc
  • Receptors, Notch
  • nicastrin protein
  • DAPI
  • APH1A protein, human
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Peptide Hydrolases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human