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

Guozhang Mao, Mei Zhen Cui, Tong Li, Yipeng Jin, Xuemin Xu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)837-844
Number of pages8
JournalJournal of Neurochemistry
Volume123
Issue number5
DOIs
StatePublished - Dec 2012

Keywords

  • APP
  • Alzheimer's disease
  • gamma-secretase
  • pen-2
  • presenilin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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