ArticleThe Journal of biological chemistry2011
Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Structure and Function of the γ-Secretase Complex.Biochemistry · 2019Article
- Structural and Chemical Biology of Presenilin Complexes.Cold Spring Harbor perspectives in medicine · 2017Review
- Structural basis of human γ-secretase assembly.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- The dynamic conformational landscape of gamma-secretase.Journal of cell science · 2015Article
- Structural biology of presenilin 1 complexes.Molecular neurodegeneration · 2014Review
- A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of γ-secretase.The Journal of biological chemistry · 2014Article
- Molecular neurodegeneration: basic biology and disease pathways.Molecular neurodegeneration · 2014Article
- Crystal structure of the γ-secretase component nicastrin.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Three-dimensional structure of human γ-secretase.Nature · 2014Article
- Perturbations of the straight transmembrane α-helical structure of the amyloid precursor protein affect its processing by γ-secretase.The Journal of biological chemistry · 2014Article
- Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.Structure (London, England : 1993) · 2014Article
- Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780.International journal of Alzheimer's disease · 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
- Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein.Biochemistry · 2013Article
- Structural biology of presenilins and signal peptide peptidases.The Journal of biological chemistry · 2013Review
- Visualizing active enzyme complexes using a photoreactive inhibitor for proximity ligation--application on γ-secretase.PloS one · 2013Article
- The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol.Science (New York, N.Y.) · 2012Article
- Development of clickable active site-directed photoaffinity probes for γ-secretase.Bioorganic & medicinal chemistry letters · 2012Article
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Authors and funding
11 authors.
Funding
Abstract
The γ-secretase membrane protein complex is responsible for proteolytic maturation of signaling precursors and catalyzes the final step in the production of the amyloid β-peptides implicated in the pathogenesis of Alzheimer disease. The incorporation of PEN-2 (presenilin enhancer 2) into a pre-activation intermediate, composed of the catalytic subunit presenilin and the accessory proteins APH-1 (anterior pharynx-defective 1) and nicastrin, triggers the endoproteolysis of presenilin and results in an active tetrameric γ-secretase. We have determined the three-dimensional reconstruction of a mature and catalytically active γ-secretase using single-particle cryo-electron microscopy. γ-Secretase has a cup-like shape with a lateral belt of ∼40-50 Å in height that encloses a water-accessible internal chamber. Active site labeling with a gold-coupled transition state analog inhibitor suggested that the γ-secretase active site faces this chamber. Comparison with the structure of a trimeric pre-activation intermediate suggested that the incorporation of PEN-2 might contribute to the maturation of the active site architecture.
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