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- PDB-6w0o: Amyloid-beta(1-40) fibril derived from Alzheimer's disease cortic... -

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Basic information

Entry
Database: PDB / ID: 6w0o
TitleAmyloid-beta(1-40) fibril derived from Alzheimer's disease cortical tissue
ComponentsAmyloid-beta precursor protein
KeywordsPROTEIN FIBRIL / amyloid-beta / Alzheimer's disease
Function / homology
Function and homology information


amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / 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 / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / 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 / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / 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 / astrocyte projection / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / positive regulation of protein metabolic process / dendrite development / TRAF6 mediated NF-kB activation / modulation of excitatory postsynaptic potential / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / main axon / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / regulation of presynapse assembly / ECM proteoglycans / positive regulation of T cell migration / neuronal dense core vesicle / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / cellular response to manganese ion / clathrin-coated pit / Notch signaling pathway / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / astrocyte activation / ionotropic glutamate receptor signaling pathway / axonogenesis / response to interleukin-1 / positive regulation of mitotic cell cycle / positive regulation of calcium-mediated signaling / protein serine/threonine kinase binding / cellular response to copper ion / platelet alpha granule lumen / cellular response to cAMP / positive regulation of glycolytic process / adult locomotory behavior / central nervous system development / positive regulation of long-term synaptic potentiation / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / endosome lumen / dendritic shaft / TAK1-dependent IKK and NF-kappa-B activation / learning / positive regulation of JNK cascade / Post-translational protein phosphorylation / locomotory behavior / microglial cell activation / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / positive regulation of non-canonical NF-kappaB signal transduction / synapse organization / cellular response to nerve growth factor stimulus / visual learning / recycling endosome / response to lead ion / positive regulation of interleukin-6 production / Golgi lumen / cognition / 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 / positive regulation of tumor necrosis factor production / Platelet degranulation / heparin binding / regulation of gene expression / regulation of translation / early endosome membrane / G alpha (i) signalling events / perikaryon / G alpha (q) signalling events / dendritic spine
Similarity search - Function
Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site ...Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / SOLID-STATE NMR / helical reconstruction / simulated annealing / cryo EM / Resolution: 2.77 Å
AuthorsGhosh, U. / Thurber, K.R. / Tycko, R.
CitationJournal: 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
DepositionMar 2, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.pdbx_database_id_DOI ..._citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 14, 2023Group: Database references / Other / Category: database_2 / pdbx_database_status
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_nmr_data
Revision 1.3May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 / Item: _database_2.pdbx_DOI

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Assembly

Deposited unit
1: Amyloid-beta precursor protein
2: Amyloid-beta precursor protein
3: Amyloid-beta precursor protein
4: Amyloid-beta precursor protein
5: Amyloid-beta precursor protein
6: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)26,0156
Polymers26,0156
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy, negative-stain TEM, unstained TEM, atomic force microscopy, cryoEM, solid state NMR, etc.
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13490 Å2
ΔGint-83 kcal/mol
Surface area10060 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 60structures with the least restraint violations
RepresentativeModel #1lowest energy
SymmetryHelical symmetry: (Circular symmetry: 1 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 6 / Rise per n subunits: 2.45 Å / Rotation per n subunits: 179.66 °)

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Components

#1: Protein/peptide
Amyloid-beta precursor protein / APP / ABPP / APPI / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta A4 ...APP / ABPP / APPI / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta A4 protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 4335.852 Da / Num. of mol.: 6 / Fragment: UNP residues 653-692 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P05067

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Experimental details

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Experiment

Experiment
Method
ELECTRON MICROSCOPY
SOLID-STATE NMR
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111anisotropic13D NCACX
121anisotropic13D NCOCX
131anisotropic13D CANCX
141anisotropic13D CONCX
151anisotropic12D 13C-13C

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Sample preparation

ComponentName: amyloid-beta(1-40) fibrils derived from human AD brain
Type: COMPLEX
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.
Entity ID: all / Source: NATURAL
Molecular weightValue: 29 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
Details: 10 mM phosphate buffer with 0.01% NaN3 to avoid microbial contamination. Buffers were filtered to avoid contamination.
Buffer componentConc.: 10 mM / Name: Phosphate buffer / Formula: Na2HPO4/NaH2PO4
SpecimenConc.: 0.45 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Protein exists in solution as amyloid fibrils of varying lengths.
Specimen supportDetails: The grids were checked in microscope prior to use. / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA PLUNGER / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 293 K
Details: The grids were preblotted for 10 seconds and blotted for 6 seconds before plunging.
DetailsType: fibrous protein
Contents: 100 uM U-15N,13C amyloid-beta(1-40), phosphate buffer
Details: lyophilized, rehydrated in MAS rotor, 100 uM concentration prior to pelleting
Label: U-labeled fibrils / Solvent system: phosphate buffer
SampleConc.: 100 uM / Component: amyloid-beta(1-40) / Isotopic labeling: U-15N,13C
Sample conditionsDetails: pelleted, lyophilized, rehydrated in MAS rotor / Ionic strength: 10 mM / Label: conditions_1 / pH: 7.4 / PH err: 0.05 / Pressure: 1 atm / Temperature: 297 K / Temperature err: 2

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Data collection

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Details: Preliminary grid screening was done manually in FEI T12.
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: -3000 nm / Nominal defocus min: -500 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Residual tilt: 6 mradians
Image recordingAverage exposure time: 10 sec. / Electron dose: 73.5 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1337
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV
Image scansMovie frames/image: 50 / Used frames/image: 1-50
NMR spectrometerType: Varian InfinityPlus / Manufacturer: Varian / Model: InfinityPlus / Field strength: 600 MHz

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Processing

EM software
IDNameVersionCategoryDetails
1RELION3particle selectionmanual picking
2SerialEMv3.7image acquisition
4GctfCTF correction
7Coot0.8.9model fittingmodel was built manually
9X-PLOR2.53model refinement
10RELION3initial Euler assignment
11MATLABinitial Euler assignment
13RELIONcustomclassificationmodified from 3.0-beta
14RELIONcustom3D reconstructionmodified from 3.0-beta
Image processingDetails: The selected images were corrected for gain. The gain reference was not rotated or flipped.
CTF correctionDetails: The correction was done in Gctf and is corrected for amplitude. Per -particle CTF refinement was done prior to final reconstruction.
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.66 ° / Axial rise/subunit: 2.45 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 19790
Details: The particles were picked using Relion manual pick, with a 20A low pass filter and particle diameter of 30A.
3D reconstructionResolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14775 / Algorithm: FOURIER SPACE
Details: A modified version of RELION 3.0-beta was used for the reconstruction. The modified version allowed local averaging of the rotation angle. Final reconstruction used 2-fold screw symmetry.
Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
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).
NMR software
NameVersionDeveloperClassification
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
SparkyGoddardchemical shift assignment
X-PLOR NIH2.53Schwieters, Kuszewski, Tjandra and Clorerefinement
RefinementMethod: simulated annealing / Software ordinal: 3
Details: phi/psi from TalosN & EM density used as restraints
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the least restraint violations
Conformers calculated total number: 60 / Conformers submitted total number: 10

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