ArticleThe Journal of biological chemistry2010
Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation.Cell reports · 2022Article
- Article
- LipoproteinmBio · 2020Article
- A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor.The Journal of cell biology · 2019Article
- Huannao Yicong Formula () regulates γ-secretase activity through APH-1 and PEN-2 gene ragulation pathways in hippocampus of APP/PS1 double transgenic mice.Chinese journal of integrative medicine · 2017Article
- Effects and Mechanism of Huannao Yicong Decoction Extract on the Ethology of Transgenic APP/PS1 Mice.Evidence-based complementary and alternative medicine : eCAM · 2017Article
- Substrate recruitment of γ-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping.The EMBO journal · 2016Article
- Aberrant expression of Notch1, HES1, and DTX1 genes in glioblastoma formalin-fixed paraffin-embedded tissues.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Nicastrin is required for amyloid precursor protein (APP) but not Notch processing, while anterior pharynx-defective 1 is dispensable for processing of both APP and Notch.Journal of neurochemistry · 2016Article
- Fluorescent Analogue of Batimastat Enables Imaging of α-Secretase in Living Cells.ACS chemical neuroscience · 2016Article
- Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis.The Journal of cell biology · 2015Article
- Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis.Biochemistry · 2014Article
- The γ-secretase complex: from structure to function.Frontiers in cellular neuroscience · 2014Review
- The very many faces of presenilins and the γ-secretase complex.Protoplasma · 2013Review
- Cellular mechanisms of γ-secretase substrate selection, processing and toxicity.Progress in neurobiology · 2012Review
- Targeting γ-secretase in breast cancer.Breast cancer (Dove Medical Press) · 2012Review
- γ-Secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines.Investigative ophthalmology & visual science · 2012Article
- Modulation of γ-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease.PloS one · 2012Article
- γ-Secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1.The Journal of biological chemistry · 2011Article
- Chemical Biology, Molecular Mechanism and Clinical Perspective of γ-Secretase Modulators in Alzheimer's Disease.Current neuropharmacology · 2011Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Gamma-secretase is a ubiquitous, multiprotein enzyme composed of presenilin, nicastrin, Aph-1, and Pen-2. It mediates the intramembrane proteolysis of many type 1 proteins, plays an essential role in numerous signaling pathways, and helps drive the pathogenesis of Alzheimer disease by excising the hydrophobic, aggregation-prone amyloid beta-peptide from the beta-amyloid precursor protein. A central unresolved question is how its many substrates bind and enter the gamma-secretase complex. Here, we provide evidence that both the beta-amyloid precursor protein holoprotein and its C-terminal fragments, the immediate substrates of gamma-secretase, can associate with Aph-1 at overexpressed as well as endogenous protein levels. This association was observed using bi-directional co-immunoprecipitation in multiple systems and detergent conditions, and an beta-amyloid precursor protein-Aph-1 complex was specifically isolated following in situ cross-linking in living cells. In addition, another endogenous canonical gamma-substrate, Jagged, showed association of both its full-length and C-terminal fragment forms with Aph-1. We were also able to demonstrate that this interaction with substrates was conserved across the multiple isoforms of Aph-1 (beta, alphaS, and alphaL), as they were all able to bind beta-amyloid precursor protein with similar affinity. Finally, two highly conserved intramembrane histidines (His-171 and His-197) within Aph-1, which were recently shown to be important for gamma-secretase activity, are required for efficient binding of substrates. Taken together, our data suggest a dominant role for Aph-1 in interacting with gamma-secretase substrates prior to their processing by the proteolytic complex.
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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.