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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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

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Presenilins
Amyloid Precursor Protein Secretases
Caenorhabditis elegans
Proteolysis
Mutation
Presenilin-2
Membranes
Amyloid beta-Protein Precursor
Drosophila
Membrane Proteins
Embryonic Structures
Maintenance
Phenotype
Association reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

A Conserved GXXXG Motif in APH-1 Is Critical for Assembly and Activity of the γ-Secretase Complex. / Lee, Sheu Fen; Shah, Sanjiv; Yu, Cong; Wigley, W. Christian; Li, Harry; Lim, Myungsil; Pedersen, Kia; Han, Weiping; Thomas, Philip; Lundkvist, Johan; Hao, Yi Heng; Yu, Gang.

In: Journal of Biological Chemistry, Vol. 279, No. 6, 06.02.2004, p. 4144-4152.

Research output: Contribution to journalArticle

Lee, SF, Shah, S, Yu, C, Wigley, WC, Li, H, Lim, M, Pedersen, K, Han, W, Thomas, P, Lundkvist, J, Hao, YH & 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, vol. 279, no. 6, pp. 4144-4152. https://doi.org/10.1074/jbc.M309745200
Lee, Sheu Fen ; Shah, Sanjiv ; Yu, Cong ; Wigley, W. Christian ; Li, Harry ; Lim, Myungsil ; Pedersen, Kia ; Han, Weiping ; Thomas, Philip ; Lundkvist, Johan ; Hao, Yi Heng ; Yu, Gang. / A Conserved GXXXG Motif in APH-1 Is Critical for Assembly and Activity of the γ-Secretase Complex. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 6. pp. 4144-4152.
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AU - Shah, Sanjiv

AU - Yu, Cong

AU - Wigley, W. Christian

AU - Li, Harry

AU - Lim, Myungsil

AU - Pedersen, Kia

AU - Han, Weiping

AU - Thomas, Philip

AU - Lundkvist, Johan

AU - Hao, Yi Heng

AU - Yu, Gang

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