The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Mechanism of the cleavage specificity of Alzheimer’s disease γ-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein
Open accessAbstract
Proteolytic processing of the amyloid precursor protein by β-secretase yields A4CT (C99), which is cleaved further by the as yet unknown γ-secretase, yielding the β-amyloid (Aβ) peptide with 40 (Aβ 40 ) or 42 residues (Aβ 42 ). Because the position of γ-secretase cleavage is crucial for the pathogenesis of Alzheimer’s disease, we individually replaced all membrane-domain residues of A4CT outside the Aβ domain with phenylalanine, stably transfected the constructs in COS7 cells, and determined the effect of these mutations on the cleavage specificity of γ-secretase (Aβ 42 /Aβ 40 ratio). Compared with wild-type A4CT, mutations at Val-44, Ile-47, and Val-50 led to decreased Aβ 42 /Aβ 40 ratios, whereas mutations at Thr-43, Ile-45, Val-46, Leu-49, and Met-51 led to increased Aβ 42 /Aβ 40 ratios. A massive effect was observed for I45F (34-fold increase) making this construct important for the generation of animal models for Alzheimer’s disease. Unlike the other mutations, A4CT-V44F was processed mainly to Aβ 38 , as determined by mass spectrometry. Our data provide a detailed model for the active site of γ-secretase: γ-secretase interacts with A4CT by binding to one side of the α-helical transmembrane domain of A4CT. Mutations in the transmembrane domain of A4CT interfere with the interaction between γ-secretase and A4CT and, thus, alter the cleavage specificity of γ-secretase.
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Cites
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Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., Iwata, N., & Saido, T. C. (2014) · Nature Neuroscience · doi:10.1038/nn.3697 · Cited by 1,366
Alzheimer's Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics
Selkoe, D. J., & Schenk, D. (2003) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140248 · Cited by 818
APP mouse models for Alzheimer’s disease preclinical studies.
Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper, B., Hardy, J., Vassar, R., Winblad, B., & Saido, T. C. (2017) · The EMBO Journal · doi:10.15252/embj.201797397 · Cited by 793
Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1
Esler, W. P., Kimberly, W. T., Ostaszewski, B. L., Diehl, T. S., Moore, C. L., Tsai, J.-Y., Rahmati, T., Xia, W., Selkoe, D. J., & Wolfe, M. S. (2000) · Nature Cell Biology · doi:10.1038/35017062 · Cited by 517
A Portrait of Alzheimer Secretases--New Features and Familiar Faces
Esler, W. P., & Wolfe, M. S. (2001) · Science · doi:10.1126/science.1064638 · Cited by 493
Metadata
- Authors
- Lichtenthaler, S. F., Wang, R., Grimm, H., Uljon, S. N., Masters, C. L., & Beyreuther, K.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1999-03-16
- Volume
- 96
- Issue
- 6
- Pages
- 3053-3058
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2146955477
- Cited by
- 234
- References
- 9
- FWCI
- 10.21
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Mechanism of the cleavage specificity of Alzheimer’s disease γ-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. https://app.cochat.ai/papers/10.1073/pnas.96.6.3053
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- Lichtenthaler, S. F., Wang, R., Grimm, H., Uljon, S. N., Masters, C. L., & Beyreuther, K. (1999). Mechanism of the cleavage specificity of Alzheimer’s disease γ-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.96.6.3053
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
