Aph-1 contributes to the stabilization and trafficking of the γ-secretase complex through mechanisms involving intermolecular and intramolecular interactions

Manabu Niimura, Noriko Isoo, Nobumasa Takasugi, Makiko Tsuruoka, Kumiko Ui-Tei, Kaoru Saigo, Yuichi Morohashi, Taisuke Tomita, Takeshi Iwatsubo

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

γ-Secretase cleaves type I transmembrane proteins, including β-amyloid precursor protein and Notch, and requires the formation of a protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2 for its activity. Aph-1 is implicated in the stabilization of this complex, although its precise mechanistic role remains unknown. Substitution of the first glycine within the transmembrane GXXXG motif of Aph-1 causes a loss-of-function phenotype in Caenorhabditis elegans. Here, using an untranslated region-targeted RNA interference/rescue strategy in Drosophila Schneider 2 cells, we show that Aph-1 contributes to the assembly of the γ-secretase complex by multiple mechanisms involving intermolecular and intramolecular interactions depending on or independent of the conserved glycines. Aph-1 binds to nicastrin forming an early subcomplex independent of the conserved glycines within the endoplasmic reticulum. Certain mutations in the conserved GXXXG motif affect the interaction of the Aph-1-nicastrin subcomplex with presenilin that mediates trafficking of the presenilin-Aph-1-nicastrin tripartite complex to the Golgi. The same mutations decrease the stability of Aph-1 polypeptides themselves, possibly by affecting intramolecular associations through the transmembrane domains. Our data suggest that the proper assembly of the Aph-1-nicastrin subcomplex with presenilin is the prerequisite for the trafficking as well as the enzymatic activity of the γ-secretase complex and that Aph-1 functions as a stabilizing scaffold in the assembly of this complex.

Original languageEnglish
Pages (from-to)12967-12975
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number13
DOIs
Publication statusPublished - Apr 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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