+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-28741 | |||||||||
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Title | Brain-derived 42-residue amyloid-beta fibril type B | |||||||||
Map data | ||||||||||
Sample |
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Keywords | amyloid-b 42 (Ab42) fibril / Alzheimer' / s disease (AD) / Polymorphism. / PROTEIN FIBRIL | |||||||||
Function / homology | Function and homology information cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / axo-dendritic transport / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / signaling receptor activator activity / axon midline choice point recognition ...cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / axo-dendritic transport / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / signaling receptor activator activity / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / Lysosome Vesicle Biogenesis / ciliary rootlet / PTB domain binding / Golgi-associated vesicle / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / dendrite development / presynaptic active zone / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / transition metal ion binding / regulation of presynapse assembly / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / negative regulation of neuron differentiation / intracellular copper ion homeostasis / ECM proteoglycans / trans-Golgi network membrane / positive regulation of T cell migration / smooth endoplasmic reticulum / spindle midzone / Purinergic signaling in leishmaniasis infection / clathrin-coated pit / protein serine/threonine kinase binding / positive regulation of chemokine production / regulation of peptidyl-tyrosine phosphorylation / forebrain development / Notch signaling pathway / neuron projection maintenance / Mitochondrial protein degradation / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / positive regulation of calcium-mediated signaling / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / cholesterol metabolic process / response to interleukin-1 / positive regulation of mitotic cell cycle / extracellular matrix organization / axonogenesis / adult locomotory behavior / platelet alpha granule lumen / positive regulation of peptidyl-threonine phosphorylation / positive regulation of interleukin-1 beta production / dendritic shaft / learning / cognition / positive regulation of long-term synaptic potentiation / central nervous system development / endosome lumen / locomotory behavior / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / synapse organization / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / TAK1-dependent IKK and NF-kappa-B activation / visual learning / neuromuscular junction / recycling endosome / positive regulation of interleukin-6 production / Golgi lumen / neuron cellular homeostasis / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / positive regulation of tumor necrosis factor production / G2/M transition of mitotic cell cycle / cell-cell junction / neuron projection development / Platelet degranulation / apical part of cell / synaptic vesicle Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.76 Å | |||||||||
Authors | Tycko R / Lee M / Yau Y-M / Louis JM | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2023 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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_28741.map.gz | 25.3 MB | EMDB map data format | |
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Header (meta data) | emd-28741-v30.xml emd-28741.xml | 17.2 KB 17.2 KB | Display Display | EMDB header |
Images | emd_28741.png | 67.1 KB | ||
Filedesc metadata | emd-28741.cif.gz | 5.8 KB | ||
Others | emd_28741_half_map_1.map.gz emd_28741_half_map_2.map.gz | 383.3 MB 383.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-28741 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-28741 | HTTPS FTP |
-Validation report
Summary document | emd_28741_validation.pdf.gz | 628.1 KB | Display | EMDB validaton report |
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Full document | emd_28741_full_validation.pdf.gz | 627.7 KB | Display | |
Data in XML | emd_28741_validation.xml.gz | 17.8 KB | Display | |
Data in CIF | emd_28741_validation.cif.gz | 21.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-28741 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-28741 | HTTPS FTP |
-Related structure data
Related structure data | 8ezeMC 8ezdC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_28741.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.86 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_28741_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_28741_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : amyloid-b 42 (Ab42) fibril
Entire | Name: amyloid-b 42 (Ab42) fibril |
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Components |
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-Supramolecule #1: amyloid-b 42 (Ab42) fibril
Supramolecule | Name: amyloid-b 42 (Ab42) fibril / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 4514.10 kDa/nm |
-Macromolecule #1: Beta-amyloid protein 42
Macromolecule | Name: Beta-amyloid protein 42 / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 4.520087 KDa |
Recombinant expression | Organism: Escherichia coli BL21(DE3) (bacteria) |
Sequence | String: DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV IA UniProtKB: Amyloid-beta precursor protein |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Concentration | 0.34 mg/mL |
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Buffer | pH: 7.4 / Component - Concentration: 10.0 mM / Component - Name: Sodium Phosphate / Details: 10mM Na-phosphate, 0.1% sodium azide |
Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Pressure: 0.039 kPa Details: The grid was glow discharged immediately before use. |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 99 % / Chamber temperature: 93 K / Instrument: FEI VITROBOT MARK I Details: Preblot for 12-13 seconds and blot for 2.5-3.0 seconds before plunging. |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 11520 pixel / Digitization - Dimensions - Height: 8184 pixel / Number grids imaged: 1 / Number real images: 5557 / Average exposure time: 1.65 sec. / Average electron dose: 50.34 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Details | Manually generated model was fit into the density using PHENIX and UCSF Chimera. Further refinements were performed using Xplor-NIH. |
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Refinement | Protocol: OTHER |
Output model | PDB-8eze: |