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Open data
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Basic information
Entry | Database: PDB / ID: 8ezd | ||||||
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Title | Brain-derived 42-residue amyloid-beta fibril type A | ||||||
![]() | Beta-amyloid protein 42 | ||||||
![]() | PROTEIN FIBRIL / amyloid-b 42 (Ab42) fibril / Alzheimer' / s disease (AD) / Polymorphism. | ||||||
Function / homology | ![]() amyloid-beta complex / microglia development / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of synapse structure or activity / axo-dendritic transport / regulation of Wnt signaling pathway ...amyloid-beta complex / microglia development / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of synapse structure or activity / axo-dendritic transport / regulation of Wnt signaling pathway / axon midline choice point recognition / astrocyte activation involved in immune response / smooth endoplasmic reticulum calcium ion homeostasis / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / ciliary rootlet / Golgi-associated vesicle / PTB domain binding / Lysosome Vesicle Biogenesis / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / suckling behavior / COPII-coated ER to Golgi transport vesicle / positive regulation of protein metabolic process / dendrite development / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / presynaptic active zone / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / regulation of presynapse assembly / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / forebrain development / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / axonogenesis / ionotropic glutamate receptor signaling pathway / positive regulation of mitotic cell cycle / cholesterol metabolic process / response to interleukin-1 / positive regulation of calcium-mediated signaling / protein serine/threonine kinase binding / platelet alpha granule lumen / positive regulation of glycolytic process / adult locomotory behavior / dendritic shaft / positive regulation of long-term synaptic potentiation / central nervous system development / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / endosome lumen / learning / locomotory behavior / astrocyte activation / positive regulation of JNK cascade / Post-translational protein phosphorylation / microglial cell activation / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / synapse organization / positive regulation of non-canonical NF-kappaB signal transduction / TAK1-dependent IKK and NF-kappa-B activation / neuromuscular junction / visual learning / recycling endosome / positive regulation of interleukin-6 production / Golgi lumen / cognition / neuron cellular homeostasis / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of inflammatory response / cellular response to amyloid-beta / neuron projection development / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / apical part of cell / synaptic vesicle / Platelet degranulation / cell-cell junction Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.83 Å | ||||||
![]() | Tycko, R. / Lee, M. / Yau, Y.-M. / Louis, J.M. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structures of brain-derived 42-residue amyloid-β fibril polymorphs with unusual molecular conformations and intermolecular interactions. Authors: Myungwoon Lee / Wai-Ming Yau / John M Louis / Robert Tycko / ![]() Abstract: Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible ...Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible molecular structures. Previous studies of Aβ42 fibrils, including fibrils prepared entirely in vitro or extracted from brain tissue and using solid-state NMR (ssNMR) or cryogenic electron microscopy (cryo-EM) methods, have found polymorphs with differences in amino acid sidechain orientations, lengths of structurally ordered segments, and contacts between cross-β subunit pairs within a single filament. Despite these differences, Aβ42 molecules adopt a common S-shaped conformation in all previously described high-resolution Aβ42 fibril structures. Here we report two cryo-EM-based structures of Aβ42 fibrils that are qualitatively different, in samples derived from AD brain tissue by seeded growth. In type A fibrils, residues 12 to 42 adopt a ν-shaped conformation, with both intra-subunit and intersubunit hydrophobic contacts to form a compact core. In type B fibrils, residues 2 to 42 adopt an υ-shaped conformation, with only intersubunit contacts and internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied K28-A42 salt bridges in type A fibrils. The coexistence of two predominant polymorphs, with differences in N-terminal dynamics, is supported by ssNMR data, as is faithful propagation of structures from first-generation to second-generation brain-seeded Aβ42 fibril samples. These results demonstrate that Aβ42 fibrils can exhibit a greater range of structural variations than seen in previous studies. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 642.8 KB | Display | ![]() |
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PDB format | ![]() | 542.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
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Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 47 KB | Display | |
Data in CIF | ![]() | 75.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 28740MC ![]() 8ezeC C: citing same article ( M: map data used to model this data |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Number of models | 9 |
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Components
#1: Protein/peptide | Mass: 4520.087 Da / Num. of mol.: 8 / Fragment: residues 672-713 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
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Sample preparation
Component | Name: amyloid-b 42 (Ab42) fibril / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Value: 4514.10 kDa/nm / Experimental value: YES |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.4 / Details: 10mM Na-phosphate, 0.1% sodium azide |
Buffer component | Conc.: 10 mM / Name: Sodium Phosphate |
Specimen | Conc.: 0.34 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK I / Cryogen name: ETHANE / Humidity: 99 % / Chamber temperature: 93 K Details: Preblot for 12-13 seconds and blot for 2.5-3.0 seconds before plunging |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 500 nm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 1.65 sec. / Electron dose: 44.65 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3383 |
Image scans | Width: 11520 / Height: 8184 / Movie frames/image: 22 |
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Processing
EM software |
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Image processing | Details: Gatan Imaging Filter (GIF) Quantum LS | ||||||||||||||||||||||||||||||||||||||||||||
CTF correction | Details: CTFFIND-4 / Type: NONE | ||||||||||||||||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -179.09 ° / Axial rise/subunit: 2.46 Å / Axial symmetry: C1 | ||||||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 374821 | ||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 68481 / Symmetry type: HELICAL | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: OTHER Details: Manually generated model was fit into the density using PHENIX and UCSF Chimera. Further refinements were performed using Xplor-NIH. |