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BACE2 functions as an alternative alpha-secretase in cells
R Yan1, J B Munzner, M E Shuck
1Department of Cell and Molecular Biology, Pharmacia Corporation, Kalamazoo, Michigan 49007, USA. ryan@pharmacia.com
The Journal of Biological Chemistry
|June 26, 2001
Summary
Beta-secretase 2 (BACE2) autoactivates and cleaves amyloid precursor protein (APP) differently in vitro versus in cells. BACE2 exhibits distinct processing and localization compared to BACE1.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- BACE1 and BACE2 are aspartyl proteases with similar structures, including a transmembrane domain.
- BACE1 is known as the Alzheimer's beta-secretase.
- BACE2 is located on chromosome 21 and is associated with Down's syndrome.
Purpose of the Study:
- To investigate the autoactivation and substrate specificity of BACE2.
- To compare the in vitro and cellular processing of amyloid precursor protein (APP) by BACE2.
- To determine the subcellular localization patterns of BACE2.
Main Methods:
- Purification and in vitro autoactivation of BACE2.
- Analysis of APP cleavage by purified BACE2 and in cellular systems.
- Investigation of BACE2 localization using chimeric constructs and various cellular compartments.
Main Results:
- Purified BACE2 undergoes autoactivation in vitro.
- BACE2 exhibits distinct APP cleavage patterns in vitro compared to cellular assays.
- BACE2 localizes to multiple cellular compartments, including the ER, Golgi, and plasma membrane, influenced by its transmembrane domain.
Conclusions:
- BACE2 autoactivates and has unique APP processing specificity distinguishing it from BACE1.
- Cellular localization influences BACE2 function but does not alter its APP processing patterns.
- BACE2 differs from BACE1 in prosegment processing, APP specificity, and subcellular localization.