S-Palmitoylation of γ-secretase subunits nicastrin and aph-1

Haipeng Cheng, Kulandaivelu S. Vetrivel, Renaldo C. Drisdel, Xavier Meckler, Ping Gong, Jae Yoon Leem, Tong Li, Meghan Carter, Ying Chen, Phuong Nguyen, Takeshi Iwatsubo, Taisuke Tomita, Philip Chun Wong, William N. Green, Maria Z. Kounnas, Gopal Thinakaran

Research output: Contribution to journalArticle

Abstract

Proteolytic processing of amyloid precursor protein (APP) by β- and γ-secretases generates β-amyloid (Aβ) peptides, which accumulate in the brains of individuals affected by Alzheimer disease. Detergent-resistant membrane microdomains (DRM) rich in cholesterol and sphingolipid, termed lipid rafts, have been implicated in Aβ production. Previously, we and others reported that the four integral subunits of the γ-secretase associate with DRM. In this study we investigated the mechanisms underlying DRM association of γ-secretase subunits. We report that in cultured cells and in brain the γ-secretase subunits nicastrin and APH-1 undergo S-palmitoylation, the post-translational covalent attachment of the long chain fatty acid palmitate common in lipid raft-associated proteins. By mutagenesis we show that nicastrin is S-palmitoylated at Cys 689, and APH-1 is S-palmitoylated at Cys 182 and Cys 245. S-Palmitoylation-defective nicastrin and APH-1 form stable γ-secretase complexes when expressed in knock-out fibroblasts lacking wild type sub-units, suggesting that S-palmitoylation is not essential for γ-secretase assembly. Nevertheless, fractionation studies show that S-palmitoylation contributes to DRM association of nicastrin and APH-1. Moreover, pulse-chase analyses reveal that S-palmitoylation is important for nascent polypeptide stability of both proteins. Co-expression of S-palmitoylation-deficient nicastrin and APH-1 in cultured cells neither affects Aβ40, Aβ42, and AICD production, nor intramembrane processing of Notch and N-cadherin. Our findings suggest that S-palmitoylation plays a role in stability and raft localization of nicastrin and APH-1, but does not directly modulate γ-secretase processing of APP and other substrates.

Original languageEnglish (US)
Pages (from-to)1373-1384
Number of pages12
JournalJournal of Biological Chemistry
Volume284
Issue number3
DOIs
StatePublished - Jan 16 2009
Externally publishedYes

Fingerprint

Lipoylation
Amyloid Precursor Protein Secretases
Membrane Microdomains
Detergents
Membranes
Cultured Cells
Brain
Processing
Cells
Lipids
Mutagenesis
Peptides
Sphingolipids
Amyloid beta-Protein Precursor
Protein Stability
Palmitates
Cadherins
Fibroblasts
Fractionation
Amyloid

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Cheng, H., Vetrivel, K. S., Drisdel, R. C., Meckler, X., Gong, P., Leem, J. Y., ... Thinakaran, G. (2009). S-Palmitoylation of γ-secretase subunits nicastrin and aph-1. Journal of Biological Chemistry, 284(3), 1373-1384. https://doi.org/10.1074/jbc.M806380200

S-Palmitoylation of γ-secretase subunits nicastrin and aph-1. / Cheng, Haipeng; Vetrivel, Kulandaivelu S.; Drisdel, Renaldo C.; Meckler, Xavier; Gong, Ping; Leem, Jae Yoon; Li, Tong; Carter, Meghan; Chen, Ying; Nguyen, Phuong; Iwatsubo, Takeshi; Tomita, Taisuke; Wong, Philip Chun; Green, William N.; Kounnas, Maria Z.; Thinakaran, Gopal.

In: Journal of Biological Chemistry, Vol. 284, No. 3, 16.01.2009, p. 1373-1384.

Research output: Contribution to journalArticle

Cheng, H, Vetrivel, KS, Drisdel, RC, Meckler, X, Gong, P, Leem, JY, Li, T, Carter, M, Chen, Y, Nguyen, P, Iwatsubo, T, Tomita, T, Wong, PC, Green, WN, Kounnas, MZ & Thinakaran, G 2009, 'S-Palmitoylation of γ-secretase subunits nicastrin and aph-1', Journal of Biological Chemistry, vol. 284, no. 3, pp. 1373-1384. https://doi.org/10.1074/jbc.M806380200
Cheng H, Vetrivel KS, Drisdel RC, Meckler X, Gong P, Leem JY et al. S-Palmitoylation of γ-secretase subunits nicastrin and aph-1. Journal of Biological Chemistry. 2009 Jan 16;284(3):1373-1384. https://doi.org/10.1074/jbc.M806380200
Cheng, Haipeng ; Vetrivel, Kulandaivelu S. ; Drisdel, Renaldo C. ; Meckler, Xavier ; Gong, Ping ; Leem, Jae Yoon ; Li, Tong ; Carter, Meghan ; Chen, Ying ; Nguyen, Phuong ; Iwatsubo, Takeshi ; Tomita, Taisuke ; Wong, Philip Chun ; Green, William N. ; Kounnas, Maria Z. ; Thinakaran, Gopal. / S-Palmitoylation of γ-secretase subunits nicastrin and aph-1. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 3. pp. 1373-1384.
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AU - Meckler, Xavier

AU - Gong, Ping

AU - Leem, Jae Yoon

AU - Li, Tong

AU - Carter, Meghan

AU - Chen, Ying

AU - Nguyen, Phuong

AU - Iwatsubo, Takeshi

AU - Tomita, Taisuke

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