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- EMDB-21501: Amyloid-beta(1-40) fibril derived from Alzheimer's disease cortic... -

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Basic information

Entry
Database: EMDB / ID: EMD-21501
TitleAmyloid-beta(1-40) fibril derived from Alzheimer's disease cortical tissue
Map dataCryoEM density map from RELION-based analysis
Sample
  • Complex: amyloid-beta(1-40) fibrils derived from human AD brain
    • Protein or peptide: Amyloid-beta precursor protein
Keywordsamyloid-beta / Alzheimer's disease / PROTEIN FIBRIL
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 / axo-dendritic transport / regulation of Wnt signaling pathway / regulation of synapse structure or activity ...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 / axo-dendritic transport / regulation of Wnt signaling pathway / regulation of synapse structure or activity / 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 / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / astrocyte projection / Lysosome Vesicle Biogenesis / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / positive regulation of protein metabolic process / TRAF6 mediated NF-kB activation / signaling receptor activator activity / Advanced glycosylation endproduct receptor signaling / negative regulation of long-term synaptic potentiation / modulation of excitatory postsynaptic potential / The NLRP3 inflammasome / main axon / transition metal ion binding / intracellular copper ion homeostasis / regulation of multicellular organism growth / ECM proteoglycans / regulation of presynapse assembly / 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 / Notch signaling pathway / clathrin-coated pit / extracellular matrix organization / neuron projection maintenance / astrocyte activation / ionotropic glutamate receptor signaling pathway / Mitochondrial protein degradation / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / axonogenesis / protein serine/threonine kinase binding / response to interleukin-1 / platelet alpha granule lumen / cellular response to copper ion / cellular response to cAMP / positive regulation of glycolytic process / central nervous system development / positive regulation of interleukin-1 beta production / dendritic shaft / endosome lumen / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / adult locomotory behavior / learning / positive regulation of JNK cascade / Post-translational protein phosphorylation / locomotory behavior / serine-type endopeptidase inhibitor activity / microglial cell activation / positive regulation of non-canonical NF-kappaB signal transduction / TAK1-dependent IKK and NF-kappa-B activation / cellular response to nerve growth factor stimulus / regulation of long-term neuronal synaptic plasticity / recycling endosome / synapse organization / visual learning / response to lead ion / positive regulation of interleukin-6 production / Golgi lumen / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / endocytosis / cellular response to amyloid-beta / neuron projection development / positive regulation of inflammatory response / positive regulation of tumor necrosis factor production / Platelet degranulation / heparin binding / regulation of translation / regulation of gene expression / 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)
Methodhelical reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsGhosh U / Thurber KR
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, 2020-
Header (metadata) releaseApr 1, 2020-
Map releaseJan 13, 2021-
UpdateMay 15, 2024-
Current statusMay 15, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6w0o
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6w0o
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21501.png

Downloads & links

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Map

FileDownload / File: emd_21501.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM density map from RELION-based analysis
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 400 pix.
= 432. Å		1.08 Å/pix.
x 400 pix.
= 432. Å		1.08 Å/pix.
x 400 pix.
= 432. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.021 / Movie #1: 0.021
Minimum - Maximum-0.0682921 - 0.13522795
Average (Standard dev.)-0.0000037405164 (±0.0031375533)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 432.00003 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z432.000432.000432.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0680.135-0.000

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Supplemental data

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Mask #1

Fileemd_21501_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : amyloid-beta(1-40) fibrils derived from human AD brain

EntireName: amyloid-beta(1-40) fibrils derived from human AD brain
Components
  • Complex: amyloid-beta(1-40) fibrils derived from human AD brain
    • Protein or peptide: Amyloid-beta precursor protein

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Supramolecule #1: amyloid-beta(1-40) fibrils derived from human AD brain

SupramoleculeName: 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.
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29 kDa/nm

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Macromolecule #1: Amyloid-beta precursor protein

MacromoleculeName: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.335852 KDa
SequenceString:
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV

UniProtKB: Amyloid-beta precursor protein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration0.45 mg/mL
BufferpH: 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.
GridModel: 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.
VitrificationCryogen 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..
DetailsProtein exists in solution as amyloid fibrils of varying lengths.

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Electron microscopy

MicroscopeTFS KRIOS
Alignment procedureComa free - Residual tilt: 6.0 mrad
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
DetailsPreliminary grid screening was done manually in FEI T12.
Image recordingFilm 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 beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 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 stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

DetailsThe selected images were corrected for gain. The gain reference was not rotated or flipped.
Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 2.45 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.66 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. custom) / Software - details: modified from 3.0-beta
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.
Number images used: 14775
Segment selectionNumber selected: 19790 / Software - Name: RELION (ver. 3.0) / Software - details: manual picking
Details: The particles were picked using Relion manual pick, with a 20A low pass filter and particle diameter of 30A.
Startup modelType of model: OTHER
Details: The initial model was taken from a lower-resolution cryoEM reconstruction of amyloid-beta(1-40) fibrils prepared without brain seeding, low-pass filtered at 10 Angstrom resolution.
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsXplor-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).
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

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

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