TY - JOUR
T1 - Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-β precursor protein and Notch
AU - Lee, Sheu Fen
AU - Shah, Sanjiv
AU - Li, Hongqiao
AU - Yu, Cong
AU - Han, Weiping
AU - Yu, Gang
PY - 2002/11/22
Y1 - 2002/11/22
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M208164200
DO - 10.1074/jbc.M208164200
M3 - Article
C2 - 12297508
AN - SCOPUS:0037160063
SN - 0021-9258
VL - 277
SP - 45013
EP - 45019
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 47
ER -