Maturation and Endosomal Targeting of β-Site Amyloid Precursor Protein-cleaving Enzyme
Open accessAbstract
The amyloidogenic Abeta peptide is liberated from the amyloid precursor protein (APP) by two proteolytic activities, beta-secretase and gamma-secretase. Recently, a type I membrane protein termed BACE (beta-site APP cleaving enzyme) with characteristics of an aspartyl protease has been identified as the beta-secretase. We undertook a series of biochemical and morphological investigations designed to characterize the basic properties of this protein. Initial studies indicated that BACE undergoes N-linked glycosylation at three of four potential sites. Metabolic pulse-chase experiments revealed that after core glycosylation, BACE is rapidly and efficiently transported to the Golgi apparatus and distal secretory pathway. BACE was also found to be quite stable, being turned over with a t(12) of approximately 16 h. Retention of BACE in the endoplasmic reticulum by introduction of a C-terminal dilysine motif prevented complex carbohydrate processing and demonstrated that propeptide cleavage occurs after exit from this organelle. BACE exhibited intramolecular disulfide bonding but did not form oligomeric structures by standard SDS-polyacrylamide gel electrophoresis analysis and sedimented as a monomer in sucrose velocity gradients. Immunofluorescence studies showed a largely vesicular staining pattern for BACE that colocalized well with endosomal, but not lysosomal, markers. Measurable levels of BACE were also detected on the plasma membrane by both immunostaining and cell surface b…
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Highest BACE1 activity is detected in acidic compartments along the secretory and endocytic pathways including endosomes and trans-Golgi.
“which is consistent with highest BACE1 activity being detected in acidic compartments along the secretory and endocytic pathways including the endosomes and trans-Golgi (Bennett et al., 2000; Huse et al., 2000, 2002; Toh et al., 2017, 2018).”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Huse et al., 2000
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- Authors
- Huse, J. T., Pijak, D. S., Leslie, G. J., Lee, V. M.-Y., & Doms, R. W.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Doms, Robert W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 275
- Issue
- 43
- Pages
- 33729-33737
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2010416572
- Cited by
- 402
- References
- 4
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 9 · 2021: 9 · 2020: 8 · 2019: 16 · 2018: 6 · 2017: 10 · 2016: 17 · 2015: 9 · 2014: 21 · 2013: 16 · 2012: 26
- FWCI
- 11.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG011542)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- BACE, beta-secretase, amyloid precursor protein, amyloid-beta, N-glycosylation, Golgi apparatus, secretory pathway, endosomal targeting, endosomes, protein stability, propeptide cleavage, intramolecular disulfide bond, dileucine motif, plasma membrane, protein trafficking
- MeSH terms
- Amino Acid Sequence, Animals, Biological Transport, Disulfides, Endocytosis, Glycosylation, Lysosomes, Molecular Sequence Data, Endopeptidases, Rabbits, Endosomes, Aspartic Acid Endopeptidases, Amino Acid Motifs, Amyloid Precursor Protein Secretases
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