Pen-2 is dispensable for endoproteolysis of presenilin 1, and nicastrin-Aph subcomplex is important for both γ-secretase assembly and substrate recruitment

J Neurochem. 2012 Dec;123(5):837-44. doi: 10.1111/jnc.12016. Epub 2012 Oct 11.


γ-secretase is a protease complex with at least four components: presenilin, nicastrin (NCT), anterior pharynx-defective 1 (Aph-1), and presenilin enhancer 2 (Pen-2). In this study, using knockout cell lines and small interfering RNA technology, our data demonstrated that the disappeared presenilin 1 C-terminal fragment (PS1C) caused by knockdown of pen-2 or knockout of NCT or Aph-1 was recovered by the addition of proteasome inhibitors, indicating that Pen-2, as well as NCT and Aph-1α, is dispensable for presenilin endoproteolysis. Our data also demonstrate that the formation of the nicastrin-Aph-1 subcomplex plays not only an important role in γ-secretase complex assembly but also in recruiting substrate C-terminal fragment of amyloid precursor protein generated by β-cleavage. Ablating any one component resulted in the instability of other components of the γ-secretase complex, and the presence of all three of the other components is required for full maturation of NCT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Blotting, Western
  • Endopeptidases / metabolism*
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • Immunoprecipitation
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Presenilin-1 / metabolism*
  • Proteolysis
  • RNA, Small Interfering


  • Membrane Glycoproteins
  • Presenilin-1
  • RNA, Small Interfering
  • nicastrin protein
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • presenilin enhancer 2, mouse