Journal
NEUROBIOLOGY OF DISEASE
Volume 14, Issue 2, Pages 194-204Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/S0969-9961(03)00123-2
Keywords
Alzheimer; presenilin; amyloid; secretase; Aph1; Pen-2; nicastrin
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Funding
- NIA NIH HHS [AG 17593] Funding Source: Medline
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gamma-Secretase is a proteolytic complex whose substrates include Notch, beta-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 gamma-secretase activity. Here, we examined the interaction of the components of the gamma-secretase complex in Chinese hamster ovary cells stably expressing human forms of APP, PSI, Aph1, and Pen-2. Subcellular fractionation of membrane vesicles and subsequent coimmunoprecipitation of individual gamma-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 P-protein and APP intracellular domain. Immunofluorescent staining of the individual gamma-secretase components supported our biochemical evidence that the gamma-secretase components assemble into the proteolytically active gamma-secretase complex in the Golgi/TGN compartment. (C) 2003 Elsevier Inc. All rights reserved.
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