ArticleThe Journal of biological chemistry2012
Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of γ-secretase.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 62 citations in OpenAlex.
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion.Molecular psychiatry · 2022Article
- An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.Biophysical journal · 2022Article
- Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis.Cancer discovery · 2022Article
- γ-Secretase in Alzheimer's disease.Experimental & molecular medicine · 2022Review
- Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Presenilin 1 phosphorylation regulates amyloid-β degradation by microglia.Molecular psychiatry · 2021Article
- Article
- A Pentacyclic Triterpene fromACS chemical neuroscience · 2020Article
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion.Langmuir : the ACS journal of surfaces and colloids · 2020Article
- Epac1 inhibition ameliorates pathological angiogenesis through coordinated activation of Notch and suppression of VEGF signaling.Science advances · 2020Article
- Expression Profiling of Notch Signalling Pathway and Gamma-Secretase Activity in the Brain of Ts1Cje Mouse Model of Down Syndrome.Journal of molecular neuroscience : MN · 2019Article
- GSAP modulates γ-secretase specificity by inducing conformational change in PS1.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Review
- A Clinical Case of Patient Carrying Rare Pathological PSEN1 Gene Mutation (L424V) Demonstrates the Phenotypic Heterogenity of Early Onset Familial AD.Frontiers in psychiatry · 2019Article
- Review
- Structural and Chemical Biology of Presenilin Complexes.Cold Spring Harbor perspectives in medicine · 2017Review
- ER-associated degradation regulates Alzheimer's amyloid pathology and memory function by modulating γ-secretase activity.Nature communications · 2017Article
- Bidirectional regulation of Aβ levels by Presenilin 1.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, and mutations in this protein cause familial Alzheimer Disease (FAD). However, little is known about how these mutations affect the active site of γ-secretase. Here, we show that PS1 mutations alter the S2 subsite within the active site of γ-secretase using a multiple photoaffinity probe approach called "photophore walking." Moreover, we developed a unique in vitro assay with a biotinylated recombinant Notch1 substrate and demonstrated that PS1 FAD mutations directly and significantly reduced γ-secretase activity for Notch1 cleavage. Substitution of the Notch Cys-1752 residue, which interacts with the S2 subsite, with Val, Met, or Ile has little effect on wild-type PS1 but leads to more efficient substrates for mutant PS1s. This study indicates that alteration of this S2 subsite plays an important role in determining the activity and specificity of γ-secretase for APP and Notch1 processing, which provides structural basis and insights on how certain PS1 FAD mutations lead to AD pathogenesis.
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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.