ArticleProceedings of the National Academy of Sciences of the United States of America2015
Structural basis of human γ-secretase assembly.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
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Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 100 citations in OpenAlex.
- Analysis of hidradenitis suppurativa-linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages.Human molecular genetics · 2019Pooled it
- Neuroinflammatory and molecular pathways in Alzheimer's disease: mechanistic crosstalk and emerging therapeutic opportunities.Inflammopharmacology · 2026Review
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- miR-151-5p regulates neural stem cell fate by targeting APH1A to modulate Notch signaling gradients.Stem cell reports · 2026Article
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Structure-activity relationship of BMS906024 derivatives for Cryptosporidium parvum growth inhibition.Bioorganic & medicinal chemistry letters · 2023Article
- Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.Communications biology · 2023Article
- The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics.International journal of biological sciences · 2023Review
- Article
- Cryo-EM structure of the human concentrative nucleoside transporter CNT3.PLoS biology · 2020Article
- γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion.Langmuir : the ACS journal of surfaces and colloids · 2020Article
- Substrate recognition and processing by γ-secretase.Biochimica et biophysica acta. Biomembranes · 2020Review
- γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors.Frontiers in aging neuroscience · 2020Article
- Involvement of a Membrane-Bound Amphiphilic Helix in Substrate Discrimination and Binding by anFrontiers in microbiology · 2020Article
- Substrate-Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype.Frontiers in molecular neuroscience · 2020Review
- Phosphorylation Signaling in APP Processing in Alzheimer's Disease.International journal of molecular sciences · 2019Review
- Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1.RSC advances · 2019Article
- The Biosynthesis, Signaling, and Neurological Functions of Bile Acids.Biomolecules · 2019Review
- GSAP modulates γ-secretase specificity by inducing conformational change in PS1.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor.The Journal of cell biology · 2019Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The four-component intramembrane protease γ-secretase is intricately linked to the development of Alzheimer's disease. Despite recent structural advances, the transmembrane segments (TMs) of γ-secretase remain to be specifically assigned. Here we report a 3D structure of human γ-secretase at 4.32-Å resolution, determined by single-particle, electron cryomicroscopy in the presence of digitonin and with a T4 lysozyme fused to the amino terminus of presenilin 1 (PS1). The overall structure of this human γ-secretase is very similar to that of wild-type γ-secretase determined in the presence of amphipols. The 20 TMs are unambiguously assigned to the four components, revealing principles of subunit assembly. Within the transmembrane region, PS1 is centrally located, with its amino-terminal fragment (NTF) packing against Pen-2 and its carboxyl-terminal fragment (CTF) interacting with Aph-1. The only TM of nicastrin associates with Aph-1 at the thick end of the TM horseshoe, and the extracellular domain of nicastrin directly binds Pen-2 at the thin end. TM6 and TM7 in PS1, which harbor the catalytic aspartate residues, are located on the convex side of the TM horseshoe. This structure serves as an important framework for understanding the function and mechanism of γ-secretase.
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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.