ArticleThe Journal of biological chemistry2005
gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site.
Article in The Journal of biological chemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 99 citations in OpenAlex.
- Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer's Disease.Molecules (Basel, Switzerland) · 2021Review
- A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling.Molecular psychiatry · 2020Article
- Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production.The Journal of biological chemistry · 2017Article
- Part 1: Notch-sparing γ-secretase inhibitors: The identification of novel naphthyl and benzofuranyl amide analogs.Bioorganic & medicinal chemistry letters · 2016Article
- Part 3: Notch-sparing γ-secretase inhibitors: SAR studies of 2-substituted aminopyridopyrimidinones.Bioorganic & medicinal chemistry letters · 2016Article
- Part 2. Notch-sparing γ-secretase inhibitors: The study of novel γ-amino naphthyl alcohols.Bioorganic & medicinal chemistry letters · 2016Article
- The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-β peptides.Scientific reports · 2015Article
- Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.Molecular neurodegeneration · 2015Article
- Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease.Neurobiology of disease · 2015Article
- Allosteric regulation of rhomboid intramembrane proteolysis.The EMBO journal · 2014Article
- Complex relationships between substrate sequence and sensitivity to alterations in γ-secretase processivity induced by γ-secretase modulators.Biochemistry · 2014Article
- Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity.PloS one · 2014Article
- Toward the structure of presenilin/γ-secretase and presenilin homologs.Biochimica et biophysica acta · 2013Review
- The role of γ-secretase activating protein (GSAP) and imatinib in the regulation of γ-secretase activity and amyloid-β generation.The Journal of biological chemistry · 2013Article
- Interplay between α-, β-, and γ-secretases determines biphasic amyloid-β protein level in the presence of a γ-secretase inhibitor.The Journal of biological chemistry · 2013Article
- Treatment strategies targeting amyloid β-protein.Cold Spring Harbor perspectives in medicine · 2012Review
- γ-Secretase inhibitors and modulators for Alzheimer's disease.Journal of neurochemistry · 2012Review
- Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease.Cold Spring Harbor perspectives in medicine · 2012Review
- Chemical Biology, Molecular Mechanism and Clinical Perspective of γ-Secretase Modulators in Alzheimer's Disease.Current neuropharmacology · 2011Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
gamma-Secretase is an unusual protease with an intramembrane catalytic site that cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor. Genetic and biochemical studies have identified four membrane proteins as components of gamma-secretase: heterodimeric presenilin composed of its N- and C-terminal fragments, nicastrin, Aph-1, and Pen-2. Here we demonstrated that certain compounds, including protein kinase inhibitors and their derivatives, act directly on purified gamma-secretase to selectively block cleavage of APP- but not Notch-based substrates. Moreover, ATP activated the generation of the APP intracellular domain and Abeta, but not the generation of the Notch intracellular domain by the purified protease complex, and was a direct competitor of the APP-selective inhibitors, as were other nucleotides. In accord, purified gamma-secretase bound specifically to an ATP-linked resin. Finally, a photoactivable ATP analog specifically labeled presenilin 1-C-terminal fragments in purified gamma-secretase preparations; the labeling was blocked by ATP itself and APP-selective gamma-secretase inhibitors. We concluded that a nucleotide-binding site exists within gamma-secretase, and certain compounds that bind to this site can specifically modulate the generation of Abeta while sparing Notch. Drugs targeting the gamma-secretase nucleotide-binding site represent an attractive strategy for safely treating Alzheimer disease.
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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.