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- EMDB-0405: Amyloid-Beta (20-34) with L-isoaspartate 23 -

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Basic information

Entry
Database: EMDB / ID: EMD-0405
TitleAmyloid-Beta (20-34) with L-isoaspartate 23
Map data
Sample
  • Complex: crystal of amyloid-beta residues 20-34 with L-isoaspartate at position 23
    • Protein or peptide: Amyloid-beta A4 protein
  • Ligand: water
Keywordsprotofilament / 2 sub 1 screw symmetry / post-translational modification / isoaspartate / 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 / Lysosome Vesicle Biogenesis / astrocyte projection / 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 / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / 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 / Mitochondrial protein degradation / astrocyte activation / ionotropic glutamate receptor signaling pathway / 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 / endosome lumen / positive regulation of interleukin-1 beta production / dendritic shaft / 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 / regulation of long-term neuronal synaptic plasticity / cellular response to nerve growth factor stimulus / 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)
Methodelectron crystallography / cryo EM
AuthorsSawaya MR / Warmack RA
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Research Resources (NIH/NCRR)5T32GM008496 United States
National Science Foundation (NSF, United States)MCB-1714569 United States
National Institutes of Health/National Center for Research Resources (NIH/NCRR)GM-007185 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Commun / Year: 2019
Title: Structure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.
Authors: Rebeccah A Warmack / David R Boyer / Chih-Te Zee / Logan S Richards / Michael R Sawaya / Duilio Cascio / Tamir Gonen / David S Eisenberg / Steven G Clarke /
Abstract: Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20- ...Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD.
History
DepositionDec 6, 2018-
Header (metadata) releaseDec 19, 2018-
Map releaseAug 7, 2019-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.1
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 1.1
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6nb9
  • Surface level: 1.1
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6nb9
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0405.png

Downloads & links

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Map

FileDownload / File: emd_0405.map.gz / Format: CCP4 / Size: 473.6 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)X (Row.)Y (Col.)
0.29 Å/pix.
x 112 pix.
= 32.738 Å		0.27 Å/pix.
x 108 pix.
= 29.203 Å		0.24 Å/pix.
x 10 pix.
= 4.87 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX: 0.2704 Å / Y: 0.2435 Å / Z: 0.2923 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.1 / Movie #1: 1.1
Minimum - Maximum-1.1124427 - 5.3232923
Average (Standard dev.)-0.000000001282909 (±0.68701303)
SymmetrySpace group: 4
Details

EMDB XML:

Map geometry
Axis orderYXZ
Origin000
Dimensions10810112
Spacing10820112
CellA: 29.2032 Å / B: 4.87 Å / C: 32.7376 Å
α: 90.0 ° / β: 101.897 ° / γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.270398148148150.24350.29230357142857
M x/y/z10820112
origin x/y/z0.0000.0000.000
length x/y/z29.2034.87032.738
α/β/γ90.000101.89790.000
start NX/NY/NZ000
NX/NY/NZ10810112
MAP C/R/S213
start NC/NR/NS000
NC/NR/NS10108112
D min/max/mean-1.1125.323-0.000

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Supplemental data

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Sample components

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Entire : crystal of amyloid-beta residues 20-34 with L-isoaspartate at pos...

EntireName: crystal of amyloid-beta residues 20-34 with L-isoaspartate at position 23
Components
  • Complex: crystal of amyloid-beta residues 20-34 with L-isoaspartate at position 23
    • Protein or peptide: Amyloid-beta A4 protein
  • Ligand: water

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Supramolecule #1: crystal of amyloid-beta residues 20-34 with L-isoaspartate at pos...

SupramoleculeName: crystal of amyloid-beta residues 20-34 with L-isoaspartate at position 23
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Molecular weightTheoretical: 6.21 kDa/nm

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Macromolecule #1: Amyloid-beta A4 protein

MacromoleculeName: Amyloid-beta A4 protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.491666 KDa
SequenceString:
FAE(IAS)VGSNKG AIIGL

UniProtKB: Amyloid-beta precursor protein

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Macromolecule #2: water

MacromoleculeName: water / type: ligand / ID: 2 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingelectron crystallography
Aggregation state3D array

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Sample preparation

Concentration2.5 mg/mL
BufferpH: 7.6 / Component - Name: water
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 30 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber temperature: 100 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample is a crystal.

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
TemperatureMin: 100.0 K / Max: 100.0 K
Image recordingFilm or detector model: FEI CETA (4k x 4k) / Digitization - Dimensions - Width: 2048 pixel / Digitization - Dimensions - Height: 2048 pixel / Number grids imaged: 2 / Number diffraction images: 159 / Average exposure time: 3.0 sec. / Average electron dose: 0.01 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Camera length: 1050 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES
Crystallography statisticsNumber intensities measured: 16529 / Number structure factors: 3946 / Fourier space coverage: 82.7 / R sym: 0.197 / R merge: 0.197 / Overall phase error: 28.4 / Overall phase residual: 0.1 / Phase error rejection criteria: 0.1 / High resolution: 1.05 Å / Shell - Shell ID: 1 / Shell - High resolution: 1.0 Å / Shell - Low resolution: 1.05 Å / Shell - Number structure factors: 315 / Shell - Phase residual: 0.1 / Shell - Fourier space coverage: 41.2 / Shell - Multiplicity: 3.09

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: OTHER / Overall B value: 10.135 / Target criteria: maximum liklihood
Output model

PDB-6nb9:
Amyloid-Beta (20-34) with L-isoaspartate 23

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