ArticleThe Journal of biological chemistry2008
Chemical cross-linking provides a model of the gamma-secretase complex subunit architecture and evidence for close proximity of the C-terminal fragment of presenilin with APH-1.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 44 citations in OpenAlex.
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics.International journal of biological sciences · 2023Review
- Unraveling the complexity of γ-secretase.Seminars in cell & developmental biology · 2020Review
- Structure and Function of the γ-Secretase Complex.Biochemistry · 2019Article
- Reduction of Aβ Generation by Schisandrin B through Restraining Beta-Secretase 1 Transcription and Translation.Medical science monitor : international medical journal of experimental and clinical research · 2018Article
- Structural basis of human γ-secretase assembly.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Three-dimensional structure of human γ-secretase.Nature · 2014Article
- 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
- Cellular mechanisms of γ-secretase substrate selection, processing and toxicity.Progress in neurobiology · 2012Review
- Contribution of the γ-secretase subunits to the formation of catalytic pore of presenilin 1 protein.The Journal of biological chemistry · 2012Article
- Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin.Neurobiology of aging · 2012Article
- Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease.Cold Spring Harbor perspectives in medicine · 2012Review
- Inhibitors of γ-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2011Article
- Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells.The Journal of biological chemistry · 2011Article
- Bioinformatics identification of modules of transcription factor binding sites in Alzheimer's disease-related genes by in silico promoter analysis and microarrays.International journal of Alzheimer's disease · 2011Article
- Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates.The Journal of biological chemistry · 2010Article
- Pharmacological analysis of Drosophila melanogaster gamma-secretase with respect to differential proteolysis of Notch and APP.Molecular pharmacology · 2010Article
- Induced dimerization of the amyloid precursor protein leads to decreased amyloid-beta protein production.The Journal of biological chemistry · 2009Article
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
Gamma-secretase is an intramembrane cleaving aspartyl protease complex intimately implicated in Alzheimer disease pathogenesis. The protease is composed of the catalytic subunit presenilin (PS1 or PS2), the substrate receptor nicastrin (NCT), and two additional subunits, APH-1 (APH-1a, as long and short splice forms (APH-1aL, APH-1aS), or APH-1b) and PEN-2. Apart from the Alzheimer disease-associated beta-amyloid precursor protein, gamma-secretase has been shown to cleave a large number of other type I membrane proteins. Despite the progress in elucidating gamma-secretase function, basic questions concerning the precise organization of its subunits, their molecular interactions, and their exact stoichiometry in the complex are largely unresolved. Here we isolated endogenous human gamma-secretase from human embryonic kidney 293 cells and investigated the subunit architecture of the gamma-secretase complex formed by PS1, NCT, APH-1aL, and PEN-2 by chemical cross-linking. Using this approach, we provide evidence for the close neighborhood of the PS1 N- and C-terminal fragments (NTF and CTF, respectively), the PS1 NTF and PEN-2, the PS1 CTF and APH-1aL, and NCT and APH-1aL. We thus identify a previously unrecognized PS1 CTF/APH-1aL interaction, verify subunit interactions deduced previously from indirect approaches, and provide a model of the gamma-secretase complex subunit architecture. Finally, we further show that, like the PS1 CTF, the PS2 CTF also interacts with APH-1aL, and we provide evidence that these interactions also occur with the other APH-1 variants, suggesting similar subunit architectures of all gamma-secretase complexes.
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