ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the γ-secretase.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 58 citations in OpenAlex.
- Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene.International journal of molecular sciences · 2022Review
- Molecular Pathogenesis and Disease-modifying Therapies of Alzheimer's Disease and Related Disorders.JMA journal · 2022Review
- Specific Mutations in Aph1 Cause γ-Secretase Activation.International journal of molecular sciences · 2022Article
- Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer's Disease.Pharmaceutics · 2021Article
- A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling.Molecular psychiatry · 2020Article
- Substrate-Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype.Frontiers in molecular neuroscience · 2020Review
- 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
- Activation of γ-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- Conformational Changes in Transmembrane Domain 4 of Presenilin 1 Are Associated with Altered Amyloid-β 42 Production.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
- Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities.The Journal of biological chemistry · 2016Article
- Cooperative roles of hydrophilic loop 1 and the C-terminus of presenilin 1 in the substrate-gating mechanism of γ-secretase.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Article
- Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis.Biochemistry · 2014Article
- Binding of longer Aβ to transmembrane domain 1 of presenilin 1 impacts on Aβ42 generation.Molecular neurodegeneration · 2014Article
- The γ-secretase complex: from structure to function.Frontiers in cellular neuroscience · 2014Review
- Toward the structure of presenilin/γ-secretase and presenilin homologs.Biochimica et biophysica acta · 2013Review
- The very many faces of presenilins and the γ-secretase complex.Protoplasma · 2013Review
- Biological function of Presenilin and its role in AD pathogenesis.Translational neurodegeneration · 2013Article
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Authors and funding
5 authors at 3 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 linked to the pathogenesis of Alzheimer's disease. Using a substituted cysteine accessibility method, we have previously shown that the hydrophilic "catalytic pore" structure of γ-secretase is formed by the transmembrane domains (TMDs) 6, 7, and 9 of presenilin 1 (PS1), the catalytic subunit of γ-secretase, within the membrane. Here, we analyzed the structure in and around the first hydrophobic region, the putative TMD1, of PS1, of which the precise function as well as three-dimensional location within γ-secretase remained unknown. We found that TMD1 is located in proximity to the catalytic GxGD and PAL motifs within the C-terminal fragment of PS1, facing directly the catalytic pore. Competition experiments using known γ-secretase inhibitors suggested that the N-terminal region of TMD1 functions as a subsite during proteolytic action of the γ-secretase. Intriguingly, binding of inhibitors affected water accessibility of residues at the membrane border of TMD1, suggesting the possibility of a dynamic motion of TMD1 during the catalytic process. Our results provide mechanistic insights into the functional role of TMD1 of PS1 in the intramembrane-cleaving activity of the γ-secretase.
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