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Maturation and Pro-peptide Cleavage of β-Secretase
Abstract
Amyloid beta-peptide is generated by two sequential proteolytic cleavages mediated by beta-secretase (BACE) and gamma-secretase. BACE was recently identified as a membrane-associated aspartyl protease. We have now analyzed the maturation and pro-peptide cleavage of BACE. Pulse-chase experiments revealed that BACE is post-translationally modified during transport to the cell surface, which can be monitored by a significant increase in the molecular mass. The increase in molecular mass is caused by complex N-glycosylation. Treatment with tunicamycin and N-glycosidase F led to a BACE derivative with a molecular weight corresponding to an unmodified version. In contrast, the mature form of BACE was resistant to endoglycosidase H treatment. The cytoplasmic tail of BACE was required for efficient maturation and trafficking through the Golgi; a BACE variant lacking the cytoplasmic tail undergoes inefficient maturation. In contrast a soluble BACE variant that does not contain a membrane anchor matured more rapidly than full-length BACE. Pro-BACE was predominantly located within the endoplasmic reticulum. Pro-peptide cleavage occurred immediately before full maturation and trafficking through the Golgi.
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Overexpression of BACE1 strongly increases β-secretory cleavage of APP already in early secretory compartments.
“Indeed, it has been shown that overexpression of BACE1 strongly increases -secretory cleavage of APP already in early secretory compartments (Capell et al., 2000;Liu et al., 2002;Lee et al., 2005)”
From GGA1 Is Expressed in the Human Brain and Affects the Generation of Amyloid β-Peptide (2006) · cites this paper as Capell et al., 2000
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Metadata
- Authors
- Capell, A., Steiner, H., Willem, M., Kaiser, H., Meyer, C., Walter, J., Lammich, S., Multhaup, G., & Haass, C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 275
- Issue
- 40
- Pages
- 30849-30854
- ISSN
- 0021-9258
- Cited by
- 205
- References
- 4
- Language
- en
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