ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2006
The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 82 citations in OpenAlex.
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Identification of presenilin mutations that have sufficient gamma-secretase proteolytic activity to mediate Notch signaling but disrupt organelle and neuronal health.Neurobiology of disease · 2025Article
- γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.Alzheimer's research & therapy · 2025Article
- Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.Communications biology · 2023Article
- Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.The Journal of biological chemistry · 2023Article
- Article
- Glitter in the Darkness? Nonfibrillar β-Amyloid Plaque Components Significantly Impact the β-Amyloid PET Signal in Mouse Models of Alzheimer Disease.Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2022Article
- Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition.eLife · 2021Article
- Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.Nature communications · 2021Article
- Article
- Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models.eLife · 2020Article
- Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation.EMBO reports · 2020Article
- Aβ oligomers trigger and accelerate Aβ seeding.Brain pathology (Zurich, Switzerland) · 2020Article
- Structure and Function of the γ-Secretase Complex.Biochemistry · 2019Article
- Review
- Environmental enrichment reverses Aβ pathology during pregnancy in a mouse model of Alzheimer's disease.Acta neuropathologica communications · 2018Article
- Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.EMBO molecular medicine · 2016Article
- The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease.Molecular neurobiology · 2016Review
- Inhibition of amyloid-β plaque formation by α-synuclein.Nature medicine · 2015Article
- γ-Secretase directly sheds the survival receptor BCMA from plasma cells.Nature communications · 2015Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gamma-secretase is a multisubunit aspartyl protease complex that catalyzes intramembrane cleavage of beta-amyloid precursor protein (APP), a substrate key to Alzheimer's disease pathogenesis, and of Notch, a substrate crucial for cell differentiation. How gamma-secretase recognizes and selects substrates is currently barely understood. Recent data suggest that its subunit nicastrin serves as an initial substrate receptor, which might subsequently forward substrates to the active site domain located in its catalytic subunit presenilin (PS), where an additional substrate binding site has been proposed. We now used an active site domain swapping approach of PS1 with its most distant homolog, spermatogenesis defective (SPE-4), to identify sequence determinants in this region. Strikingly, when the active site domain of PS1 was exchanged with that of SPE-4, the chimeric protein, PS1/SPE-4(6/7), supported APP but not Notch processing. In addition, PS1/SPE-4(6/7) was strongly impaired in Caenorhabditis elegans Notch signaling in vivo. Mapping experiments identified a single amino acid at position x of the GxGD motif, which contains one of the two active site aspartates, to be responsible for the observed defect in Notch processing and signaling. Our data thus implicate a role of the GxGD motif in catalytic function and substrate identification of gamma-secretase.
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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.