Functional γ-secretase complex assembly in Golgi/ trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and γ-secretase substrates

γ-Secretase is a proteolytic complex whose substrates include Notch, β-amyloid precursor protein (APP), and several other type I transmembrane proteins. Presenilin (PS) and nicastrin are known components of this high-molecular-weight complex, and recent genetic screens in invertebrates have identifi...

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Bibliographic Details
Published in:Neurobiology of disease 2003-11, Vol.14 (2), p.194-204
Main Authors: Baulac, Stephanie, LaVoie, Matthew J, Kimberly, W.Taylor, Strahle, Jennifer, Wolfe, Michael S, Selkoe, Dennis J, Xia, Weiming
Format: Article
Language:English
Subjects:
Alzheimer
Amyloid
Amyloid Precursor Protein Secretases
Animals
Aph1
Aspartic Acid Endopeptidases
CHO Cells
Cricetinae
Endopeptidases - biosynthesis
Endopeptidases - metabolism
Endopeptidases - physiology
Humans
Membrane Glycoproteins - biosynthesis
Membrane Glycoproteins - metabolism
Membrane Glycoproteins - physiology
Membrane Proteins - biosynthesis
Membrane Proteins - metabolism
Membrane Proteins - physiology
Nicastrin
Pen-2
Peptide Hydrolases
Presenilin
Presenilin-1
Secretase
trans-Golgi Network - chemistry
trans-Golgi Network - metabolism
trans-Golgi Network - physiology
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Summary:γ-Secretase is a proteolytic complex whose substrates include Notch, β-amyloid precursor protein (APP), and several other type I transmembrane proteins. Presenilin (PS) and nicastrin are known components of this high-molecular-weight complex, and recent genetic screens in invertebrates have identified two additional gene products, Aph1 and Pen-2, as key factors in γ-secretase activity. Here, we examined the interaction of the components of the γ-secretase complex in Chinese hamster ovary cells stably expressing human forms of APP, PS1, Aph1, and Pen-2. Subcellular fractionation of membrane vesicles and subsequent coimmunoprecipitation of individual γ-secretase components revealed that interactions among all proteins occurred in the Golgi/ trans-Golgi network (TGN) compartments. Furthermore, incubation of the Golgi/TGN-enriched vesicles resulted in de novo generation of amyloid β-protein and APP intracellular domain. Immunofluorescent staining of the individual γ-secretase components supported our biochemical evidence that the γ-secretase components assemble into the proteolytically active γ-secretase complex in the Golgi/TGN compartment.
ISSN:0969-9961
1095-953X
DOI:10.1016/S0969-9961(03)00123-2