The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state
Open accessAbstract
γ-Secretase is a membrane-associated protease that cleaves within the transmembrane region of amyloid precursor protein to generate the C termini of the two Aβ peptide isoforms, Aβ40 and Aβ42. Here we report the detergent solubilization and partial characterization of γ-secretase. The activity of solubilized γ-secretase was measured with a recombinant substrate, C100Flag, consisting largely of the C-terminal fragment of amyloid precursor protein downstream of the β-secretase cleavage site. Cleavage of C100Flag by γ-secretase was detected by electrochemiluminescence using antibodies that specifically recognize the Aβ40 or Aβ42 termini. Incubation of C100Flag with HeLa cell membranes or detergent-solubilized HeLa cell membranes generates both the Aβ40 and Aβ42 termini. Recovery of catalytically competent, soluble γ-secretase critically depends on the choice of detergent; CHAPSO (3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate) but not Triton X-100 is suitable. Solubilized γ-secretase activity is inhibited by pepstatin and more potently by a novel aspartyl protease transition-state analog inhibitor that blocks formation of Aβ40 and Aβ42 in mammalian cells. Upon gel exclusion chromatography, solubilized γ-secretase activity coelutes with presenilin 1 (PS1) at an apparent relative molecular weight of approximately 2.0 × 10 6 . Anti-PS1 antibody immunoprecipitates γ-secretase activity from the solubilized γ-secretase preparation. These data suggest that γ-secretase activity is catalyzed by a PS1-containing macromolecular complex.
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Cites
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Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
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Water-soluble Aβ(N-40, N-42) oligomers in normal and Alzheimer disease brains
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Cited by
APP processing in Alzheimer’s disease.
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Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
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Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
Li, Y.-M., Xu, M., Lai, M.-T., Huang, Q., Castro, J. L., DiMuzio-Mower, J., Harrison, T., Lellis, C., Nadin, A., Neduvelil, J. G., et al. (2000) · Nature · doi:10.1038/35015085 · Cited by 866
Self-citationFassbender, K., Simons, M., Bergmann, C., Stroick, M., Lütjohann, D., Keller, P., Runz, H., Kühl, S., Bertsch, T., von Bergmann, K., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.081620098 · Cited by 860
γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in?
Sisodia, S. S., & St George-Hyslop, P. H. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn785 · Cited by 512
Metadata
- Authors
- Li, Y.-M., Lai, M.-T., Xu, M., Huang, Q., DiMuzio-Mower, J., Sardana, M. K., Shi, X.-P., Yin, K.-C., Shafer, J. A., & Gardell, S. J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2000-05-09
- Volume
- 97
- Issue
- 11
- Pages
- 6138-6143
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2128084592
- Cited by
- 525
- References
- 7
- FWCI
- 36.10
- Type
- journal article
- Language
- en
- Open access
- green
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- Li, Y.-M., Lai, M.-T., Xu, M., Huang, Q., DiMuzio-Mower, J., Sardana, M. K., Shi, X.-P., Yin, K.-C., Shafer, J. A., & Gardell, S. J. (2000). Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.110126897
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