Abeta42-to-Abeta40- and angiotensin-converting activities in different domains of angiotensin-converting enzyme

Amyloid beta-protein 1-42 (Abeta42) is believed to play a causative role in the development of Alzheimer disease (AD), although it is a minor part of Abeta. In contrast, Abeta40 is the predominant secreted form of Abeta and recent studies have suggested that Abeta40 has neuroprotective effects and i...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-11, Vol.284 (46), p.31914
Main Authors: Zou, Kun, Maeda, Tomoji, Watanabe, Atsushi, Liu, Junjun, Liu, Shuyu, Oba, Ryutaro, Satoh, Yoh-ichi, Komano, Hiroto, Michikawa, Makoto
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - metabolism
Angiotensins - metabolism
Animals
Blotting, Western
Captopril - pharmacology
Catalytic Domain
Chlorocebus aethiops
COS Cells
Enalaprilat - pharmacology
Glycosylation
Humans
Mutation - genetics
Peptide Fragments - metabolism
Peptidyl-Dipeptidase A - genetics
Peptidyl-Dipeptidase A - metabolism
Protein Structure, Tertiary
Recombinant Proteins - genetics
Recombinant Proteins - isolation & purification
Recombinant Proteins - metabolism
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Summary:Amyloid beta-protein 1-42 (Abeta42) is believed to play a causative role in the development of Alzheimer disease (AD), although it is a minor part of Abeta. In contrast, Abeta40 is the predominant secreted form of Abeta and recent studies have suggested that Abeta40 has neuroprotective effects and inhibits amyloid deposition. We have reported that angiotensin-converting enzyme (ACE) converts Abeta42 to Abeta40, and its inhibition enhances brain Abeta42 deposition (Zou, K., Yamaguchi, H., Akatsu, H., Sakamoto, T., Ko, M., Mizoguchi, K., Gong, J. S., Yu, W., Yamamoto, T., Kosaka, K., Yanagisawa, K., and Michikawa, M. (2007) J. Neurosci. 27, 8628-8635). ACE has two homologous domains, each having a functional active site. In the present study, we identified the domain of ACE, which is responsible for converting Abeta42 to Abeta40. Interestingly, Abeta42-to-Abeta40-converting activity is solely found in the N-domain of ACE and the angiotensin-converting activity is found predominantly in the C-domain of ACE. We also found that the N-linked glycosylation is essential for both Abeta42-to-Abeta40- and angiotensin-converting activities and that unglycosylated ACE rapidly degraded. The domain-specific converting activity of ACE suggests that ACE inhibitors could be designed to specifically target the angiotensin-converting C-domain, without inhibiting the Abeta42-to-Abeta40-converting activity of ACE or increasing neurotoxic Abeta42.
ISSN:1083-351X
DOI:10.1074/jbc.M109.011437