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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


regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis ...regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / regulation of Wnt signaling pathway / mating behavior / positive regulation of amyloid fibril formation / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / : / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / presynaptic active zone / nuclear envelope lumen / modulation of excitatory postsynaptic potential / suckling behavior / COPII-coated ER to Golgi transport vesicle / dendrite development / smooth endoplasmic reticulum / regulation of NMDA receptor activity / TRAF6 mediated NF-kB activation / negative regulation of long-term synaptic potentiation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / regulation of presynapse assembly / The NLRP3 inflammasome / intracellular copper ion homeostasis / transition metal ion binding / regulation of multicellular organism growth / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / forebrain development / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / cholesterol metabolic process / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / neuron projection maintenance / positive regulation of glycolytic process / extracellular matrix organization / positive regulation of mitotic cell cycle / response to interleukin-1 / axonogenesis / adult locomotory behavior / trans-Golgi network membrane / dendritic shaft / locomotory behavior / platelet alpha granule lumen / positive regulation of peptidyl-threonine phosphorylation / learning / positive regulation of interleukin-1 beta production / central nervous system development / positive regulation of long-term synaptic potentiation / astrocyte activation / endosome lumen / Post-translational protein phosphorylation / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / positive regulation of JNK cascade / TAK1-dependent IKK and NF-kappa-B activation / neuromuscular junction / visual learning / serine-type endopeptidase inhibitor activity / recycling endosome / cognition / positive regulation of inflammatory response / positive regulation of interleukin-6 production / neuron cellular homeostasis / Golgi lumen / endocytosis / positive regulation of non-canonical NF-kappaB signal transduction / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron projection development / cellular response to amyloid-beta / positive regulation of DNA-binding transcription factor activity / G2/M transition of mitotic cell cycle / cell-cell junction / synaptic vesicle / positive regulation of tumor necrosis factor production / regulation of translation
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. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / 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 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

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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
Water0
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 FIELDBright-field microscopy / 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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