ArticleThe Journal of biological chemistry
Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 42 citations in OpenAlex.
- Andrographolide targets syndecan4 to impair its interaction with syntenin and inhibits the biogenesis of small extracellular vesicles.The Journal of biological chemistry · 2026Article
- Plasma levels of an N-terminal tau fragment predict Alzheimer's and neurodegenerative disease biomarkers in autosomal dominant Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Presenilin-1 Familial Alzheimer Mutations Impair γ-Secretase Cleavage of APP Through Stabilized Enzyme-Substrate Complex Formation.Biomolecules · 2025Article
- Article
- The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production.bioRxiv : the preprint server for biology · 2024Article
- γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).The Lancet. Neurology · 2024Observational
- Review
- Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.Cell reports · 2024Article
- Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease.Aging and disease · 2024Review
- Molecular Dynamics Activation of γ-Secretase for Cleavage of the Notch1 Substrate.ACS chemical neuroscience · 2023Article
- Observational
- Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease.International journal of molecular sciences · 2023Review
- Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2023Article
- Proteostasis and neurodegeneration: a closer look at autophagy in Alzheimer's disease.Frontiers in aging neuroscience · 2023Review
- Enzyme-substrate interface targeting by imidazole-based γ-secretase modulators activates γ-secretase and stabilizes its interaction with APP.The EMBO journal · 2022Article
- Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic Aβ Peptides.Molecular neurobiology · 2022Article
- Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates.Biomedicines · 2022Review
- RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons.Progress in neurobiology · 2022Article
- Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene.International journal of molecular sciences · 2022Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
γ-Secretase is responsible for the proteolysis of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer's disease (AD). The biochemical mechanism of how processing by γ-secretase is regulated, especially as regards the interaction between enzyme and substrate, remains largely unknown. Here, mutagenesis reveals that the hydrophilic loop-1 (HL-1) of presenilin-1 (PS1) is critical for both γ-secretase step-wise cleavages (processivity) and its allosteric modulation by heterocyclic γ-modulatory compounds. Systematic mutagenesis of HL-1, including all of its familial AD mutations and additional engineered variants, and quantification of the resultant Aβ products show that HL-1 is necessary for proper sequential γ-secretase processivity. We identify Y106, L113, and Y115 in HL-1 as key targets for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides. Further, we confirm that the GxxxG domain in the APP transmembrane region functions as a critical substrate motif for γ-secretase processivity: a G29A substitution in APP-C99 mimics the beneficial effects of GSMs. Together, these findings provide a molecular basis for the structural regulation of γ-processivity by enzyme and substrate, facilitating the rational design of new GSMs that lower AD-initiating amyloidogenic Aβ peptides.
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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.