Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
Abstract
Cleavage of amyloid precursor protein (APP) by the beta- and gamma-secretases generates the amino and carboxy termini, respectively, of the A beta amyloidogenic peptides A beta40 and A beta42--the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of gamma-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease increase the production of A beta42 (refs 4-6), the more amyloidogenic peptide; gamma-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in transmembrane segments of PS1 inactivates the ability of gamma-secretase to catalyse processing of APP within its transmembrane domain. It is unknown, however, whether PS1 (which has little or no homology to any known aspartyl protease) is itself a transmembrane aspartyl protease or a gamma-secretase cofactor, or helps to colocalize gamma-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent gamma-secretase inhibitors that were designed to function as transition state analogue inhibitors directed to the active site of an aspartyl protease. This observation indicates that PS1 (and PS2) may contain the active site of gamma-secretase. Interestingly, the intact, single-chain form of wild-type PS1 is not labelled by an active-site-directed photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl protease zymogen.
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- Authors
- 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., Register, R. B., Sardana, M. K., Shearman, M. S., Smith, A. L., Shi, X.-P., Yin, K.-C., Shafer, J. A., & Gardell, S. J.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- MSD (UK) Limited (United Kingdom) (GB)
- Corresponding author
- Gardell, Stephen J.
- Venue
- Nature
- Published
- 2000-06
- Volume
- 405
- Issue
- 6787
- Pages
- 689-694
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1480987708
- Cited by
- 866
- References
- 22
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 9 · 2023: 5 · 2022: 17 · 2021: 9 · 2020: 24 · 2019: 14 · 2018: 8 · 2017: 23 · 2016: 27 · 2015: 17 · 2014: 22 · 2013: 21 · 2012: 25
- FWCI
- 64.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- gamma-secretase inhibitors, presenilin 1, presenilin 2, photoaffinity labeling, amyloid-beta, Alzheimer's disease, APP processing, transition-state inhibitors, zymogen
- MeSH terms
- Alzheimer Disease, Binding Sites, Biotin, Enzyme Inhibitors, HeLa Cells, Humans, Membrane Proteins, Endopeptidases, Photochemistry, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Photoaffinity Labels, Presenilin-1, Presenilin-2, Amyloid Precursor Protein Secretases
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