ArticleProceedings of the National Academy of Sciences of the United States of America2006
Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
75 citing papers in PubMed, 160 citations in OpenAlex.
- Structure and mechanism of the γ-secretase intramembrane protease complex.Current opinion in structural biology · 2022Review
- γ-Secretase in Alzheimer's disease.Experimental & molecular medicine · 2022Review
- Design of Transmembrane Mimetic Structural Probes to Trap Different Stages of γ-Secretase-Substrate Interaction.Journal of medicinal chemistry · 2021Article
- Structure and Function of the γ-Secretase Complex.Biochemistry · 2019Article
- Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators.The EMBO journal · 2019Article
- Structural and Chemical Biology of Presenilin Complexes.Cold Spring Harbor perspectives in medicine · 2017Review
- Physiological and pathological roles of the γ-secretase complex.Brain research bulletin · 2016Review
- Nicastrin functions to sterically hinder γ-secretase-substrate interactions driven by substrate transmembrane domain.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities.The Journal of biological chemistry · 2016Article
- 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
- 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
- Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in renal cell carcinoma.Oncology letters · 2014Article
- Side-chain to main-chain hydrogen bonding controls the intrinsic backbone dynamics of the amyloid precursor protein transmembrane helix.Biophysical journal · 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
- Structural characterization of the mechanosensitive channel candidate MCA2 from Arabidopsis thaliana.PloS one · 2014Article
15 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Gamma-secretase is an intramembrane-cleaving aspartyl protease required for the normal development of metazoans because it processes Notch within cellular membranes to release its signaling domain. More than two dozen additional substrates of diverse functions have been reported, including the Notch ligands Delta and Jagged, N- and E-cadherins, and a sodium channel subunit. The protease is causally implicated in Alzheimer's disease because it releases the neurotoxic amyloid beta-peptide (Abeta) from its precursor, APP. Gamma-secretase occurs as a large complex containing presenilin (bearing the active site aspartates), nicastrin, Aph-1, and Pen-2. Because the complex contains at least 18 transmembrane domains, crystallographic approaches to its structure are difficult and remote. We recently purified the human complex essentially to homogeneity from stably expressing mammalian cells. Here, we use EM and single-particle image analysis on the purified enzyme, which produces physiological ratios of Abeta40 and Abeta42, to obtain structural information on an intramembrane protease. The 3D EM structure revealed a large, cylindrical interior chamber of approximately 20-40 A in length, consistent with a proteinaceous proteolytic site that is occluded from the hydrophobic environment of the lipid bilayer. Lectin tagging of the nicastrin ectodomain enabled proper orientation of the globular, approximately 120-A-long complex within the membrane and revealed approximately 20-A pores at the top and bottom that provide potential exit ports for cleavage products to the extra- and intracellular compartments. Our reconstructed 3D map provides a physical basis for hydrolysis of transmembrane substrates within a lipid bilayer and release of the products into distinct subcellular compartments.
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Registered trials
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.