ArticleProceedings of the National Academy of Sciences of the United States of America2010
Activation and intrinsic gamma-secretase activity of presenilin 1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
98 citing papers in PubMed, 134 citations in OpenAlex.
- Article
- Notch signaling without the APH-2/nicastrin subunit of gamma secretase in Caenorhabditis elegans germline stem cells.Genetics · 2024Article
- Supported Biomembrane Systems Incorporating Multiarm Polymers and Bioorthogonal Tethering.Langmuir : the ACS journal of surfaces and colloids · 2024Article
- Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- γ-Secretase fanning the fire of innate immunity.Biochemical Society transactions · 2023Review
- Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease.International journal of molecular sciences · 2023Article
- Application of polymersomes in membrane protein study and drug discovery: Progress, strategies, and perspectives.Bioengineering & translational medicine · 2023Review
- γ-Secretase in Alzheimer's disease.Experimental & molecular medicine · 2022Review
- Turning the tide on Alzheimer's disease: modulation of γ-secretase.Cell & bioscience · 2022Review
- Crenigacestat (LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcificationFrontiers in cardiovascular medicine · 2022Article
- Covalent fragment inhibits intramembrane proteolysis.Frontiers in molecular biosciences · 2022Article
- Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations.International journal of molecular sciences · 2021Article
- Levistolide A Attenuates Alzheimer's Pathology Through Activation of the PPARγ Pathway.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
- The dark side of Alzheimer's disease: unstructured biology of proteins from the amyloid cascade signaling pathway.Cellular and molecular life sciences : CMLS · 2020Article
- Article
- A Pentacyclic Triterpene fromACS chemical neuroscience · 2020Article
- Recent developments of small molecule γ-secretase modulators for Alzheimer's disease.RSC medicinal chemistry · 2020Review
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- Hybrid PET/MRI enables high-spatial resolution, quantitative imaging of amyloid plaques in an Alzheimer's disease mouse model.Scientific reports · 2020Article
- γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion.Langmuir : the ACS journal of surfaces and colloids · 2020Article
38 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
A complex composed of presenilin (PS), nicastrin, PEN-2, and APH-1 is absolutely required for γ-secretase activity in vivo. Evidence has emerged to suggest a role for PS as the catalytic subunit of γ-secretase, but it has not been established that PS is catalytically active in the absence of associated subunits. We now report that bacterially synthesized, recombinant PS (rPS) reconstituted into liposomes exhibits γ-secretase activity. Moreover, an rPS mutant that lacks a catalytic aspartate residue neither exhibits reconstituted γ-secretase activity nor interacts with a transition-state γ-secretase inhibitor. Importantly, we demonstrate that rPS harboring mutations that cause early onset familial Alzheimer's disease (FAD) lead to elevations in the ratio of Aβ42 to Aβ40 peptides produced from a wild-type APP substrate and that rPS enhances the Aβ42/Aβ40 peptide ratio from FAD-linked mutant APP substrates, findings that are entirely consistent with the results obtained in in vivo settings. Thus, γ-secretase cleavage specificity is an inherent property of the polypeptide. Finally, we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of γ-secretase. Thus, we conclusively establish that activated PS is catalytically competent and the bimolecular interaction of PS1 and PEN2 can convert the PS1 zymogen to an active protease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.