ArticleProceedings of the National Academy of Sciences of the United States of America2016
Nicastrin functions to sterically hinder γ-secretase-substrate interactions driven by substrate transmembrane domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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Who cites it
83 citing papers in PubMed.
- Targeting mannosylation of nicastrin N-glycans attenuates γ-secretase activity and notch-dependent leukemia progression.The Journal of clinical investigation · 2026Article
- Article
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Conformational Flexibility of Transmembrane Helices: How it Works and Where it Matters.Chemical reviews · 2026Review
- Inhibitory proteins ofJournal of bacteriology · 2025Article
- γ-Secretase-Mediated Endoproteolysis of Neuregulin-1 and E-Cadherin.Biochemistry · 2025Article
- Charting γ-secretase substrates by explainable AI.Nature communications · 2025Article
- The N-terminal PA domains of signal-peptide-peptidase-like 2 (SPPL2) proteases impact on TNFα cleavage.Communications biology · 2025Article
- Implications of Mucin-TypeMolecules (Basel, Switzerland) · 2025Review
- Pathways and Molecular Mechanisms Governing LDL Receptor Regulation.Circulation research · 2025Review
- Effects of Transmembrane Phenylalanine Residues on γ-Secretase-Mediated Notch-1 Proteolysis.ACS chemical neuroscience · 2025Article
- Cryo-EM structure of the bacterial intramembrane metalloprotease RseP in the substrate-bound state.Science advances · 2025Article
- Expression of nicastrin, NICD1, and Hes1 in NCSTN knockout mice: implications for hidradenitis suppurativa, Alzheimer's, and liver cancer.European journal of medical research · 2024Article
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- A Non-Canonical p75HER2 Signaling Pathway Underlying Trastuzumab Action and Resistance in Breast Cancer.Cells · 2024Article
- Article
- Notch signaling without the APH-2/nicastrin subunit of gamma secretase in Caenorhabditis elegans germline stem cells.Genetics · 2024Article
- Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation.Biochemical Society transactions · 2024Article
- APP-BACE1 Interaction and Intracellular Localization Regulate Aβ Production in iPSC-Derived Cortical Neurons.Cellular and molecular neurobiology · 2023Article
- Interaction of Substrates with γ-Secretase at the Level of Individual Transmembrane Helices-A Methodological Approach.International journal of molecular sciences · 2023Article
23 more citing papers are in PubMed but not listed here.
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5 authors.
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Abstract
γ-Secretase is an intramembrane-cleaving protease that processes many type-I integral membrane proteins within the lipid bilayer, an event preceded by shedding of most of the substrate's ectodomain by α- or β-secretases. The mechanism by which γ-secretase selectively recognizes and recruits ectodomain-shed substrates for catalysis remains unclear. In contrast to previous reports that substrate is actively recruited for catalysis when its remaining short ectodomain interacts with the nicastrin component of γ-secretase, we find that substrate ectodomain is entirely dispensable for cleavage. Instead, γ-secretase-substrate binding is driven by an apparent tight-binding interaction derived from substrate transmembrane domain, a mechanism in stark contrast to rhomboid--another family of intramembrane-cleaving proteases. Disruption of the nicastrin fold allows for more efficient cleavage of substrates retaining longer ectodomains, indicating that nicastrin actively excludes larger substrates through steric hindrance, thus serving as a molecular gatekeeper for substrate binding and catalysis.
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