ArticleACS central science2020
Mechanisms of γ-Secretase Activation and Substrate Processing.
Article in ACS central science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
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The trial behind it
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.Briefings in bioinformatics · 2026Review
- Review
- Presenilin, γ-Secretase, and the Search for Pathogenic Triggers of Alzheimer's Disease.Biochemistry · 2025Review
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- Unveiling Conformational States of CDK6 Caused by Binding of Vcyclin Protein and Inhibitor by Combining Gaussian Accelerated Molecular Dynamics and Deep Learning.Molecules (Basel, Switzerland) · 2024Article
- Amyloid-β and Phosphorylated Tau are the Key Biomarkers and Predictors of Alzheimer's Disease.Aging and disease · 2024Review
- 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
- Molecular Dynamics Activation of γ-Secretase for Cleavage of the Notch1 Substrate.ACS chemical neuroscience · 2023Article
- GS-SMD server for steered molecular dynamics of peptide substrates in the active site of the γ-secretase complex.Nucleic acids research · 2023Article
- Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.Communications biology · 2023Article
- Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production.International journal of molecular sciences · 2023Article
- Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.Communications biology · 2023Article
- A thermodynamic investigation of amyloid precursor protein processing by human γ-secretase.Communications biology · 2022Article
- Gaussian Accelerated Molecular Dynamics in OpenMM.The journal of physical chemistry. B · 2022Article
- Structure and mechanism of the γ-secretase intramembrane protease complex.Current opinion in structural biology · 2022Review
- Article
- Mechanism of Tripeptide Trimming of Amyloid β-Peptide 49 by γ-Secretase.Journal of the American Chemical Society · 2022Article
- GLOW: A Workflow Integrating Gaussian-Accelerated Molecular Dynamics and Deep Learning for Free Energy Profiling.Journal of chemical theory and computation · 2022Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Amyloid β-peptide, the principal component of characteristic cerebral plaques of Alzheimer's disease (AD), is produced through intramembrane proteolysis of the amyloid precursor protein (APP) by γ-secretase. Despite the importance in the pathogenesis of AD, the mechanisms of intramembrane proteolysis and substrate processing by γ-secretase remain poorly understood. Here, complementary all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method and biochemical experiments were combined to investigate substrate processing of wildtype and mutant APP by γ-secretase. The GaMD simulations captured spontaneous activation of γ-secretase, with hydrogen bonded catalytic aspartates and water poised for proteolysis of APP at the ε cleavage site. Furthermore, GaMD simulations revealed that familial AD mutations I45F and T48P enhanced the initial ε cleavage between residues Leu49-Val50, while M51F mutation shifted the ε cleavage site to the amide bond between Thr48-Leu49. Detailed analysis of the GaMD simulations allowed us to identify distinct low-energy conformational states of γ-secretase, different secondary structures of the wildtype and mutant APP substrate, and important active-site subpockets for catalytic function of the enzyme. The simulation findings were highly consistent with experimental analyses of APP proteolytic products using mass spectrometry and Western blotting. Taken together, the GaMD simulations and biochemical experiments have enabled us to elucidate the mechanisms of γ-secretase activation and substrate processing, which should facilitate rational computer-aided drug design targeting this functionally important enzyme.
Identifiers
What Socratic 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 Socratic graph.