ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
Cooperative roles of hydrophilic loop 1 and the C-terminus of presenilin 1 in the substrate-gating mechanism of γ-secretase.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 47 citations in OpenAlex.
- Interaction of Substrates with γ-Secretase at the Level of Individual Transmembrane Helices-A Methodological Approach.International journal of molecular sciences · 2023Article
- Specific Mutations in Aph1 Cause γ-Secretase Activation.International journal of molecular sciences · 2022Article
- Mass spectrometry analysis of tau and amyloid-beta in iPSC-derived models of Alzheimer's disease and dementia.Journal of neurochemistry · 2021Review
- Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis.Cell reports · 2021Article
- Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta.Molecular psychiatry · 2020Article
- Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature.RSC advances · 2020Article
- Mechanisms of γ-Secretase Activation and Substrate Processing.ACS central science · 2020Article
- PathogenicDiagnostics (Basel, Switzerland) · 2020Article
- Involvement of a Membrane-Bound Amphiphilic Helix in Substrate Discrimination and Binding by anFrontiers in microbiology · 2020Article
- Substrate-Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype.Frontiers in molecular neuroscience · 2020Review
- 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
- Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators.The EMBO journal · 2019Article
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- Structural Analysis of Target Protein by Substituted Cysteine Accessibility Method.Bio-protocol · 2018Article
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- Efficient production of a mature and functional gamma secretase protease.Scientific reports · 2018Article
- Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies.Nature reviews. Neurology · 2018Review
- Allosteric Modulation of Intact γ-Secretase Structural Dynamics.Biophysical journal · 2017Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase is a multisubunit protease complex that is responsible for generating amyloid-β peptides, which are associated with Alzheimer disease. The catalytic subunit of γ-secretase is presenilin 1 (PS1), which contains an initial substrate-binding site that is distinct from the catalytic site. Processive cleavage is suggested in the intramembrane-cleaving mechanism of γ-secretase. However, it largely remains unknown as to how γ-secretase recognizes its substrate during proteolysis. Here, we identified that the α-helical structural region of hydrophilic loop 1 (HL1) and the C-terminal region of human PS1 are distinct substrate-binding sites. Mutational analyses revealed that substrate binding to the HL1 region is critical for both ε- and γ-cleavage, whereas binding to the C-terminal region hampers γ-cleavage. Moreover, we propose that substrate binding triggers conformational changes in PS1, rendering it suitable for catalysis. Our data provide new insights into the complicated catalytic mechanism of PS1.
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