ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2017
Activation of γ-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 30 citations in OpenAlex.
- Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform.Nature communications · 2024Article
- New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.The EMBO journal · 2024Review
- Stem cell therapy in Alzheimer's disease: current status and perspectives.Frontiers in neuroscience · 2024Review
- Specific Mutations in Aph1 Cause γ-Secretase Activation.International journal of molecular sciences · 2022Article
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- 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
- A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling.Molecular psychiatry · 2020Article
- 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
- Structural Analysis of Target Protein by Substituted Cysteine Accessibility Method.Bio-protocol · 2018Article
- Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides.The Journal of biological chemistryArticle
- γ-secretase targeting in Alzheimer's disease.Journal of Alzheimer's disease reportsReview
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase is an intramembrane cleaving protease that is responsible for the generation of amyloid-β peptides, which are linked to the pathogenesis of Alzheimer disease. Recently, γ-secretase modulators (GSMs) have been shown to specifically decrease production of the aggregation-prone and toxic longer Aβ species, and concomitantly increase the levels of shorter Aβ. We previously found that phenylimidazole-type GSMs bind to presenilin 1 (PS1), the catalytic subunit of the γ-secretase, and allosterically modulate γ-secretase activity. However, the precise conformational alterations in PS1 remained unclear. Here we mapped the amino acid residues in PS1 that is crucial for the binding and pharmacological actions of E2012, a phenylimidazole-type GSM, using photoaffinity labeling and the substituted cysteine accessibility method. We also demonstrated that a piston-like vertical motion of transmembrane domain (TMD) 1 occurs during modulation of Aβ production. Taking these results together, we propose a model for the molecular mechanism of phenylimidazole-type GSMs, in which the trimming activity of γ-secretase is modulated by the position of the TMD1 of PS1 in the lipid bilayer.
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