ArticleeLife2016
The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase.
Article in eLife, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
84 citing papers in PubMed, 1 synthesis or guideline pooled it, 149 citations in OpenAlex.
- Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites.Frontiers in neuroscience · 2022Pooled it
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- A C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide.Neurobiology of disease · 2026Article
- Proteome-Based Biomarkers for Alzheimer's Disease: Old Acquisitions and Innovative Proposals.International journal of molecular sciences · 2025Review
- γ-Secretase-Mediated Endoproteolysis of Neuregulin-1 and E-Cadherin.Biochemistry · 2025Article
- Charting γ-secretase substrates by explainable AI.Nature communications · 2025Article
- Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes.Molecular neurodegeneration · 2025Article
- Effects of Transmembrane Phenylalanine Residues on γ-Secretase-Mediated Notch-1 Proteolysis.ACS chemical neuroscience · 2025Article
- Proposed Therapeutic Strategy to Combat Alzheimer's Disease by Targeting Beta and Gamma Secretases.Current Alzheimer research · 2025Review
- CRISPR/Cas9-Based therapeutics as a promising strategy for management of Alzheimer's disease: progress and prospects.Frontiers in cellular neuroscience · 2025Review
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- Article
- A Snake Venom Peptide and Its Derivatives Prevent AβACS chemical neuroscience · 2024Article
- Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.bioRxiv : the preprint server for biology · 2024Article
- Co-treatment with the seed ofFood science & nutrition · 2024Article
- Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.Cell reports · 2024Article
- Conformational Changes and Unfolding of β-Amyloid Substrates in the Active Site of γ-Secretase.International journal of molecular sciences · 2024Article
- miR-3940-5p reduces amyloid β production via selectively targetingFrontiers in aging neuroscience · 2024Article
- Molecular Dynamics Activation of γ-Secretase for Cleavage of the Notch1 Substrate.ACS chemical neuroscience · 2023Article
- APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release.The EMBO journal · 2023Article
24 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer's disease (AD). Despite considerable interest in developing γ-secretase targeting therapeutics for the treatment of AD, the precise mechanism by which γ-secretase produces Aβ has remained elusive. Herein, we demonstrate that γ-secretase catalysis is driven by the stabilization of an enzyme-substrate scission complex via three distinct amino-acid-binding pockets in the enzyme's active site, providing the mechanism by which γ-secretase preferentially cleaves APP in three amino acid increments. Substrate occupancy of these three pockets occurs after initial substrate binding but precedes catalysis, suggesting a conformational change in substrate may be required for cleavage. We uncover and exploit substrate cleavage preferences dictated by these three pockets to investigate the mechanism by which familial Alzheimer's disease mutations within APP increase the production of pathogenic Aβ species.
Indexed as
Identifiers
What OpenQuestion holds
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.