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Yorodumi- PDB-8x54: Cryo-EM structure of human gamma-secretase in complex with APP-C99 -
+Open data
-Basic information
Entry | Database: PDB / ID: 8x54 | ||||||
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Title | Cryo-EM structure of human gamma-secretase in complex with APP-C99 | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / Intramembrane protease / gamma-secretase / presenilin-1 / MEMBRANE PROTEIN-HYDROLASE complex | ||||||
Function / homology | Function and homology information Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of coagulation / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / protein catabolic process at postsynapse ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of coagulation / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / central nervous system myelination / synaptic vesicle targeting / negative regulation of axonogenesis / membrane protein intracellular domain proteolysis / regulation of resting membrane potential / choline transport / T cell activation involved in immune response / skin morphogenesis / growth factor receptor binding / NOTCH4 Activation and Transmission of Signal to the Nucleus / regulation of synaptic vesicle cycle / dorsal/ventral neural tube patterning / neural retina development / myeloid dendritic cell differentiation / L-glutamate import across plasma membrane / endoplasmic reticulum calcium ion homeostasis / Regulated proteolysis of p75NTR / regulation of phosphorylation / metanephros development / locomotion / brain morphogenesis / NMDA selective glutamate receptor signaling pathway / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / axo-dendritic transport / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / nuclear outer membrane / signaling receptor activator activity / skeletal system morphogenesis / amyloid precursor protein metabolic process / myeloid cell homeostasis / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / regulation of canonical Wnt signaling pathway / astrocyte activation involved in immune response / regulation of long-term synaptic potentiation / embryonic limb morphogenesis / regulation of spontaneous synaptic transmission / cell fate specification / mating behavior / aggresome / glutamate receptor signaling pathway / Lysosome Vesicle Biogenesis / ciliary rootlet / azurophil granule membrane / regulation of postsynapse organization / PTB domain binding / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / G protein-coupled dopamine receptor signaling pathway / Golgi-associated vesicle / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / Golgi cisterna membrane / positive regulation of amyloid fibril formation / neuron remodeling / COPII-coated ER to Golgi transport vesicle / adult behavior / mitochondrial transport / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / positive regulation of dendritic spine development / positive regulation of receptor recycling / suckling behavior / nuclear envelope lumen / blood vessel development / regulation of neuron projection development / heart looping / dendrite development / amyloid precursor protein catabolic process / cerebral cortex cell migration / protein glycosylation / presynaptic active zone / modulation of excitatory postsynaptic potential / amyloid-beta formation / TRAF6 mediated NF-kB activation / The NLRP3 inflammasome / neuromuscular process controlling balance / Advanced glycosylation endproduct receptor signaling / negative regulation of apoptotic signaling pathway / transition metal ion binding / membrane protein ectodomain proteolysis / regulation of presynapse assembly / negative regulation of long-term synaptic potentiation Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å | ||||||
Authors | Guo, X. / Yan, C. / Lei, J. / Zhou, R. / Shi, Y. | ||||||
Funding support | China, 1items
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Citation | Journal: Science / Year: 2024 Title: Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Authors: Xuefei Guo / Haotian Li / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi / Abstract: Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step ...Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step size of three residues. To elucidate the underlying mechanism, we determined the atomic structures of human γ-secretase bound individually to APP-C99, Aβ49, Aβ46, and Aβ43. In all cases, the substrate displays the same structural features: a transmembrane α-helix, a three-residue linker, and a β-strand that forms a hybrid β-sheet with presenilin 1 (PS1). Proteolytic cleavage occurs just ahead of the substrate β-strand. Each cleavage is followed by unwinding and translocation of the substrate α-helix by one turn and the formation of a new β-strand. This mechanism is consistent with existing biochemical data and may explain the cleavages of other substrates by γ-secretase. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8x54.cif.gz | 265.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8x54.ent.gz | 206.4 KB | Display | PDB format |
PDBx/mmJSON format | 8x54.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8x54_validation.pdf.gz | 963.4 KB | Display | wwPDB validaton report |
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Full document | 8x54_full_validation.pdf.gz | 984.8 KB | Display | |
Data in XML | 8x54_validation.xml.gz | 30.5 KB | Display | |
Data in CIF | 8x54_validation.cif.gz | 44.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/x5/8x54 ftp://data.pdbj.org/pub/pdb/validation_reports/x5/8x54 | HTTPS FTP |
-Related structure data
Related structure data | 38061MC 8x52C 8x53C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 3 types, 3 molecules EAB
#1: Protein | Mass: 13816.627 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Production host: Homo sapiens (human) / References: UniProt: P05067 |
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#2: Protein | Mass: 78473.555 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: NCSTN, KIAA0253, UNQ1874/PRO4317 / Production host: Homo sapiens (human) / References: UniProt: Q92542 |
#3: Protein | Mass: 52712.551 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSEN1, AD3, PS1, PSNL1 / Production host: Homo sapiens (human) References: UniProt: P49768, Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases |
-Gamma-secretase subunit ... , 2 types, 2 molecules CD
#4: Protein | Mass: 29017.943 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: APH1A, PSF, CGI-78, UNQ579/PRO1141 / Production host: Homo sapiens (human) / References: UniProt: Q96BI3 |
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#5: Protein | Mass: 12038.029 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSENEN, PEN2, MDS033 / Production host: Homo sapiens (human) / References: UniProt: Q9NZ42 |
-Sugars , 3 types, 12 molecules
#6: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #7: Polysaccharide | beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose | Source method: isolated from a genetically manipulated source #8: Sugar | ChemComp-NAG / |
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-Non-polymers , 2 types, 6 molecules
#9: Chemical | #10: Chemical | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Human gamma-secretase in complex with APP-C99 / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1500 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 822574 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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