A Conserved GXXXG Motif in APH-1 Is Critical for Assembly and Activity of the γ-Secretase Complex

Sheu Fen Lee, Sanjiv Shah, Cong Yu, W. Christian Wigley, Harry Li, Myungsil Lim, Kia Pedersen, Weiping Han, Philip Thomas, Johan Lundkvist, Yi Heng Hao, Gang Yu

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88 Scopus citations

Abstract

The multipass membrane protein APH-1, found in the γ-secretase complex together with presenilin, nicastrin, and PEN-2, is essential for Notch signaling in Caenorhabditis elegans embryos and is required for intramembrane proteolysis of Notch and β-amyloid precursor protein in mammalian and Drosophila cells. In C. elegans, a mutation of the conserved transmembrane Gly123 in APH-1 (mutant or28) leads to a notch/glp-1 loss-of-function phenotype. In this study, we show that the corresponding mutation in mammalian APH-1aL (G122D) disrupts the physical interaction of APH-1aL with hypoglycosylated immature nicastrin and the presenilin holoprotein as well as with mature nicastrin, presenilin, and PEN-2. The G122D mutation also reduced γ-secretase activity in intramembrane proteolysis of membrane-tethered Notch. Moreover, we found that the conserved transmembrane Gly122, Gly126, and Gly 130 in the fourth transmembrane region of mammalian APH-1a L are part of the membrane helix-helix interaction GXXXG motif and are essential for the stable association of APH-1aL with presenilin, nicastrin, and PEN-2. These findings suggest that APH-1 plays a GXXXG-dependent scaf-folding role in both the initial assembly and subsequent maturation and maintenance of the active γ-secretase complex.

Original languageEnglish (US)
Pages (from-to)4144-4152
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number6
DOIs
StatePublished - Feb 6 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lee, S. F., Shah, S., Yu, C., Wigley, W. C., Li, H., Lim, M., Pedersen, K., Han, W., Thomas, P., Lundkvist, J., Hao, Y. H., & Yu, G. (2004). A Conserved GXXXG Motif in APH-1 Is Critical for Assembly and Activity of the γ-Secretase Complex. Journal of Biological Chemistry, 279(6), 4144-4152. https://doi.org/10.1074/jbc.M309745200