Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Maturation and pro-peptide cleavage of β-secretase

J Biol Chem 275(40): 30849-54

Authors/Editors: Capell A
Steiner H
Willem M
Kaiser H
Meyer C
Walter J
Lammich S
Multhaup G
Haass C
Publication Date: 2000
Type of Publication: Journal Article

Amyloid β-peptide is generated by two sequential proteolytic cleavages mediated by β-secretase (BACE) and γ-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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