ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2016
Conformational Changes in Transmembrane Domain 4 of Presenilin 1 Are Associated with Altered Amyloid-β 42 Production.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016. 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, 25 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
- Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.The Journal of biological chemistry · 2023Article
- Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene.International journal of molecular sciences · 2022Review
- An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.Biophysical journal · 2022Article
- Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature.RSC advances · 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
- Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1.RSC advances · 2019Article
- Influence of membrane lipid composition on the structure and activity of γ-secretase.Physical chemistry chemical physics : PCCP · 2018Article
- Structural Analysis of Target Protein by Substituted Cysteine Accessibility Method.Bio-protocol · 2018Article
- Characterizing the structural ensemble of γ-secretase using a multiscale molecular dynamics approach.Chemical science · 2017Article
- Interrelationship between Changes in the Amyloid β 42/40 Ratio and Presenilin 1 Conformation.Molecular medicine (Cambridge, Mass.) · 2016Article
- 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
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase is an intramembrane-cleaving protease that produces amyloid-β peptide 42 (Aβ42), which is the toxic and aggregation-prone species of Aβ that causes Alzheimer's disease. Here, we used the substituted cysteine accessibility method to analyze the structure of transmembrane domains (TMDs) 4 and 5 of human presenilin 1 (PS1), a catalytic subunit of γ-secretase. We revealed that TMD4 and TMD5 face the intramembranous hydrophilic milieu together with TMD1, TMD6, TMD7, and TMD9 of PS1 to form the catalytic pore structure. Notably, we found a correlation in the distance between the cytosolic sides of TMD4/TMD7 and Aβ42 production levels, suggesting that allosteric conformational changes of the cytosolic side of TMD4 affect Aβ42-generating γ-secretase activity. Our results provide new insights into the relationship between the structure and activity of human PS1. SIGNIFICANCE STATEMENT: Modulation of γ-secretase activity to reduce toxic amyloid-β peptide species is one plausible therapeutic approaches for Alzheimer's disease. However, precise mechanistic information of γ-secretase still remains unclear. Here we identified the conformational changes in transmembrane domains of presenilin 1 that affect the proteolytic activity of the γ-secretase. Our results highlight the importance of understanding the structural dynamics of presenilin 1 in drug development against Alzheimer's disease.
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