ArticleJournal of the American Chemical Society2013
The backbone dynamics of the amyloid precursor protein transmembrane helix provides a rationale for the sequential cleavage mechanism of γ-secretase.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Alzheimer's Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective.International journal of molecular sciences · 2025Review
- Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease.Annual review of biophysics · 2024Review
- Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase.Communications biology · 2023Article
- Effect of Cholesterol on C99 Dimerization: Revealed by Molecular Dynamics Simulations.Frontiers in molecular biosciences · 2022Article
- Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.iScience · 2020Article
- Impact of Cholesterol Concentration and Lipid Phase on Structure and Fluctuation of Amyloid Precursor Protein.The journal of physical chemistry. B · 2020Article
- γ-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics.The EMBO journal · 2020Article
- Bicelles Rich in both Sphingolipids and Cholesterol and Their Use in Studies of Membrane Proteins.Journal of the American Chemical Society · 2020Article
- Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer's Therapeutics.International journal of molecular sciences · 2020Review
- Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer's Disease.Frontiers in aging neuroscience · 2020Review
- β-Amyloid aggregation and heterogeneous nucleation.Protein science : a publication of the Protein Society · 2019Review
- Modulating Hinge Flexibility in the APP Transmembrane Domain Alters γ-Secretase Cleavage.Biophysical journal · 2019Article
- Influence of the familial Alzheimer's disease-associated T43I mutation on the transmembrane structure and γ-secretase processing of the C99 peptide.The Journal of biological chemistry · 2019Article
- Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer's Disease Mutant of APP.Scientific reports · 2019Article
- Structure of APP-C99Biochimica et biophysica acta. Biomembranes · 2018Article
- Both positional and chemical variables controlThe Journal of biological chemistry · 2018Article
- Dissecting conformational changes in APP's transmembrane domain linked to ε-efficiency in familial Alzheimer's disease.PloS one · 2018Article
- Backbone Hydrogen Bond Strengths Can Vary Widely in Transmembrane Helices.Journal of the American Chemical Society · 2017Article
- Structural and biochemical differences between the Notch and the amyloid precursor protein transmembrane domains.Science advances · 2017Article
- DNA polymerase β contains a functional nuclear localization signal at its N-terminus.Nucleic acids research · 2017Article
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12 authors.
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Abstract
The etiology of Alzheimer's disease depends on the relative abundance of different amyloid-β (Aβ) peptide species. These peptides are produced by sequential proteolytic cleavage within the transmembrane helix of the 99 residue C-terminal fragment of the amyloid precursor protein (C99) by the intramembrane protease γ-secretase. Intramembrane proteolysis is thought to require local unfolding of the substrate helix, which has been proposed to be cleaved as a homodimer. Here, we investigated the backbone dynamics of the substrate helix. Amide exchange experiments of monomeric recombinant C99 and of synthetic transmembrane domain peptides reveal that the N-terminal Gly-rich homodimerization domain exchanges much faster than the C-terminal cleavage region. MD simulations corroborate the differential backbone dynamics, indicate a bending motion at a diglycine motif connecting dimerization and cleavage regions, and detect significantly different H-bond stabilities at the initial cleavage sites. Our results are consistent with the following hypotheses about cleavage of the substrate: First, the GlyGly hinge may precisely position the substrate within γ-secretase such that its catalytic center must start proteolysis at the known initial cleavage sites. Second, the ratio of cleavage products formed by subsequent sequential proteolysis could be influenced by differential extents of solvation and by the stabilities of H-bonds at alternate initial sites. Third, the flexibility of the Gly-rich domain may facilitate substrate movement within the enzyme during sequential proteolysis. Fourth, dimerization may affect substrate processing by decreasing the dynamics of the dimerization region and by increasing that of the C-terminal part of the cleavage region.
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