ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2008
The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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78 citing papers in PubMed, 145 citations in OpenAlex.
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Structural insights into human signal peptide peptidase.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production.bioRxiv : the preprint server for biology · 2024Article
- The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Interaction of Substrates with γ-Secretase at the Level of Individual Transmembrane Helices-A Methodological Approach.International journal of molecular sciences · 2023Article
- γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer's Disease.Reports of biochemistry & molecular biology · 2023Article
- A NovelJournal of Alzheimer's disease reports · 2023Article
- Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.Nature communications · 2022Article
- Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene.International journal of molecular sciences · 2022Review
- A thermodynamic investigation of amyloid precursor protein processing by human γ-secretase.Communications biology · 2022Article
- Molecular Pathogenesis and Disease-modifying Therapies of Alzheimer's Disease and Related Disorders.JMA journal · 2022Review
- Structure and mechanism of the γ-secretase intramembrane protease complex.Current opinion in structural biology · 2022Review
- Specific Mutations in Aph1 Cause γ-Secretase Activation.International journal of molecular sciences · 2022Article
- Role of cholesterol in substrate recognition by [Formula: see text]-secretase.Scientific reports · 2021Article
- Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer's Disease.Pharmaceutics · 2021Article
- A Novel Probable Pathogenic PSEN2 Mutation p.Phe369Ser Associated With Early-Onset Alzheimer's Disease in a Chinese Han Family: A Case Report.Frontiers in aging neuroscience · 2021Article
- Evolutionary History of Alzheimer Disease-Causing Protein Family Presenilins with Pathological Implications.Journal of molecular evolution · 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
18 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gamma-secretase is an unusual membrane-embedded protease, which cleaves the transmembrane domains (TMDs) of type I membrane proteins, including amyloid-beta precursor protein and Notch receptor. We have previously shown the existence of a hydrophilic pore formed by TMD6 and TMD7 of presenilin 1 (PS1), the catalytic subunit of gamma-secretase, within the membrane by the substituted cysteine accessibility method. Here we analyzed the structure of TMD8, TMD9, and the C terminus of PS1, which encompass the conserved PAL motif and the hydrophobic C-terminal tip, both being critical for the catalytic activity and the formation of the gamma-secretase complex. We found that the amino acid residues around the PAL motif and the extracellular/luminal portion of TMD9 are highly water accessible and located in proximity to the catalytic pore. Furthermore, the region starting from the luminal end of TMD9 toward the C terminus forms an amphipathic alpha-helix-like structure that extends along the interface between the membrane and the extracellular milieu. Competition analysis using gamma-secretase inhibitors revealed that the TMD9 is involved in the initial binding of substrates, as well as in the subsequent catalytic process as a subsite. Our results provide mechanistic insights into the role of TMD9 in the formation of the catalytic pore and the substrate entry, crucial to the unusual mode of intramembrane proteolysis by gamma-secretase.
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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.