ArticleJournal of cell science2015
The dynamic conformational landscape of gamma-secretase.
Article in Journal of cell science, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
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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.
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.
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Who cites it
36 citing papers in PubMed, 57 citations in OpenAlex.
- Article
- From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.Briefings in bioinformatics · 2026Review
- Article
- The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer.ACS pharmacology & translational science · 2023Review
- CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's diseaseMolecular therapy. Nucleic acids · 2022Article
- Structure and mechanism of the γ-secretase intramembrane protease complex.Current opinion in structural biology · 2022Review
- The Genomic Architecture of Hidradenitis Suppurativa-A Systematic Review.Frontiers in genetics · 2022Review
- Nanoscale organization of Nicastrin, the substrate receptor of the γ-secretase complex, as independent molecular domains.Molecular brain · 2021Article
- The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex.Biomolecules · 2021Article
- Article
- Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature.RSC advances · 2020Article
- Super-resolution microscopy reveals majorly mono- and dimeric presenilin1/γ-secretase at the cell surface.eLife · 2020Article
- Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Structure and Function of the γ-Secretase Complex.Biochemistry · 2019Article
- Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1.RSC advances · 2019Article
- Influence of membrane lipid composition on the structure and activity of γ-secretase.Physical chemistry chemical physics : PCCP · 2018Article
- Review
- Efficient production of a mature and functional gamma secretase protease.Scientific reports · 2018Article
- Article
- Dynamic Nature of presenilin1/γ-Secretase: Implication for Alzheimer's Disease Pathogenesis.Molecular neurobiology · 2018Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
Abstract
The structure and function of the gamma-secretase proteases are of great interest because of their crucial roles in cellular and disease processes. We established a novel purification protocol for the gamma-secretase complex that involves a conformation- and complex-specific nanobody, yielding highly pure and active enzyme. Using single particle electron microscopy, we analyzed the gamma-secretase structure and its conformational variability. Under steady-state conditions, the complex adopts three major conformations, which differ in overall compactness and relative position of the nicastrin ectodomain. Occupancy of the active or substrate-binding sites by inhibitors differentially stabilizes subpopulations of particles with compact conformations, whereas a mutation linked to familial Alzheimer disease results in enrichment of extended-conformation complexes with increased flexibility. Our study presents the csecretase complex as a dynamic population of interconverting conformations, involving rearrangements at the nanometer scale and a high level of structural interdependence between subunits. The fact that protease inhibition or clinical mutations, which affect amyloid beta (Abeta) generation, enrich for particular subpopulations of conformers indicates the functional relevance of the observed dynamic changes, which are likely to be instrumental for highly allosteric behavior of the enzyme.
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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.