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Yorodumi- EMDB-21501: Amyloid-beta(1-40) fibril derived from Alzheimer's disease cortic... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-21501 | |||||||||
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Title | Amyloid-beta(1-40) fibril derived from Alzheimer's disease cortical tissue | |||||||||
Map data | CryoEM density map from RELION-based analysis | |||||||||
Sample |
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Keywords | amyloid-beta / Alzheimer's disease / PROTEIN FIBRIL | |||||||||
Function / homology | Function and homology information 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 / signaling receptor activator activity ...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 / 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 / Lysosome Vesicle Biogenesis / ciliary rootlet / PTB domain binding / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / Golgi-associated vesicle / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / neuron remodeling / COPII-coated ER to Golgi transport vesicle / suckling behavior / nuclear envelope lumen / dendrite development / presynaptic active zone / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / The NLRP3 inflammasome / neuromuscular process controlling balance / Advanced glycosylation endproduct receptor signaling / transition metal ion binding / regulation of presynapse assembly / negative regulation of long-term synaptic potentiation / negative regulation of neuron differentiation / regulation of multicellular organism growth / intracellular copper ion homeostasis / ECM proteoglycans / trans-Golgi network membrane / smooth endoplasmic reticulum / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / clathrin-coated pit / protein serine/threonine kinase binding / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / 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 / cholesterol metabolic process / positive regulation of calcium-mediated signaling / ionotropic glutamate receptor signaling pathway / response to interleukin-1 / positive regulation of glycolytic process / axonogenesis / positive regulation of mitotic cell cycle / extracellular matrix organization / adult locomotory behavior / platelet alpha granule lumen / positive regulation of interleukin-1 beta production / learning / positive regulation of peptidyl-threonine phosphorylation / dendritic shaft / positive regulation of long-term synaptic potentiation / cognition / central nervous system development / endosome lumen / locomotory behavior / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / serine-type endopeptidase inhibitor activity / TAK1-dependent IKK and NF-kappa-B activation / visual learning / neuromuscular junction / recycling endosome / positive regulation of interleukin-6 production / Golgi lumen / positive regulation of inflammatory response / neuron cellular homeostasis / 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 / neuron projection development / cell-cell junction / Platelet degranulation / synaptic vesicle / apical part of cell Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.77 Å | |||||||||
Authors | Ghosh U / Thurber KR | |||||||||
Citation | Journal: Proc Natl Acad Sci U S A / Year: 2021 Title: Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue. Authors: Ujjayini Ghosh / Kent R Thurber / Wai-Ming Yau / Robert Tycko / Abstract: Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report ...Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_21501.map.gz | 224.1 MB | EMDB map data format | |
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Header (meta data) | emd-21501-v30.xml emd-21501.xml | 14.3 KB 14.3 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_21501_fsc.xml | 14.1 KB | Display | FSC data file |
Images | emd_21501.png | 120.4 KB | ||
Masks | emd_21501_msk_1.map | 244.1 MB | Mask map | |
Filedesc metadata | emd-21501.cif.gz | 6.1 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-21501 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-21501 | HTTPS FTP |
-Validation report
Summary document | emd_21501_validation.pdf.gz | 529.6 KB | Display | EMDB validaton report |
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Full document | emd_21501_full_validation.pdf.gz | 529.2 KB | Display | |
Data in XML | emd_21501_validation.xml.gz | 13.9 KB | Display | |
Data in CIF | emd_21501_validation.cif.gz | 18.7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21501 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21501 | HTTPS FTP |
-Related structure data
Related structure data | 6w0oMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_21501.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | CryoEM density map from RELION-based analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_21501_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : amyloid-beta(1-40) fibrils derived from human AD brain
Entire | Name: amyloid-beta(1-40) fibrils derived from human AD brain |
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Components |
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-Supramolecule #1: amyloid-beta(1-40) fibrils derived from human AD brain
Supramolecule | Name: amyloid-beta(1-40) fibrils derived from human AD brain type: complex / ID: 1 / Parent: 0 / Macromolecule list: all Details: Fibrils produced by seeded growth using amyloid-beta in brain extract as the source of seeds. CryoEM and solid state NMR measurements were performed on second-generation seeded fibrils. |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 29 kDa/nm |
-Macromolecule #1: Amyloid-beta precursor protein
Macromolecule | Name: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 4.335852 KDa |
Sequence | String: DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV 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 | 0.45 mg/mL |
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Buffer | pH: 7.4 / Component - Concentration: 10.0 mM / Component - Formula: Na2HPO4/NaH2PO4 / Component - Name: Phosphate buffer Details: 10 mM phosphate buffer with 0.01% NaN3 to avoid microbial contamination. Buffers were filtered to avoid contamination. |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: OTHER / Pretreatment - Pressure: 0.036000000000000004 kPa / Details: The grids were checked in microscope prior to use. |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: LEICA PLUNGER Details: The grids were preblotted for 10 seconds and blotted for 6 seconds before plunging.. |
Details | Protein exists in solution as amyloid fibrils of varying lengths. |
-Electron microscopy
Microscope | TFS KRIOS |
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Alignment procedure | Coma free - Residual tilt: 6.0 mrad |
Specialist optics | Energy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV |
Details | Preliminary grid screening was done manually in FEI T12. |
Image recording | Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-50 / Number grids imaged: 1 / Number real images: 1337 / Average exposure time: 10.0 sec. / Average electron dose: 73.5 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: -3.0 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 | Xplor-NIH was used to combine EM density with phi/psi restraints from NMR chemical shifts (from Talos-N Version 4.21 Rev 2016.343.11.31). |
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Refinement | Space: REAL / Protocol: AB INITIO MODEL |
Output model | PDB-6w0o: |