Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-β precursor protein and Notch

Sheu Fen Lee, Sanjiv Shah, Hongqiao Li, Cong Yu, Weiping Han, Gang Yu

Research output: Contribution to journalArticle

181 Citations (Scopus)

Abstract

Presenilin and nicastrin are essential components of the γ-secretase complex that is required for the intramembrane proteolysis of an increasing number of membrane proteins including the amyloid-β precursor protein (APP) and Notch. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian APH-1 (mAPH-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino-and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous mAPH-1 using small interfering RNAs results in the decrease of presenilin levels, accumulation of γ-secretase substrates (APP carboxyl-terminal fragments), and reduction of γ-secretase products (amyloid-β peptides and the intracellular domains of APP and Notch). These data indicate that mAPH-1 is probably a functional component of the γ-secretase complex required for the intramembrane proteolysis of APP and Notch.

Original languageEnglish (US)
Pages (from-to)45013-45019
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number47
DOIs
StatePublished - Nov 22 2002

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Presenilins
Proteolysis
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Membrane Proteins
Nickel
Immunoprecipitation
Amyloid
Small Interfering RNA
Rats
Brain
Cells
Cell Line
Peptides
Substrates

ASJC Scopus subject areas

  • Biochemistry

Cite this

Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-β precursor protein and Notch. / Lee, Sheu Fen; Shah, Sanjiv; Li, Hongqiao; Yu, Cong; Han, Weiping; Yu, Gang.

In: Journal of Biological Chemistry, Vol. 277, No. 47, 22.11.2002, p. 45013-45019.

Research output: Contribution to journalArticle

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AU - Han, Weiping

AU - Yu, Gang

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