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- EMDB-0619: Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation -

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Basic information

Entry
Database: EMDB / ID: EMD-0619
TitleAmyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation
Map dataAmyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation
Sample
  • Complex: Fibrils of Amyloid Beta segment 16-26
    • Protein or peptide: Amyloid-beta precursor protein
Keywordsamyloid / PROTEIN FIBRIL
Function / homology
Function and homology information


amyloid-beta complex / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of synapse structure or activity / axo-dendritic transport ...amyloid-beta complex / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of synapse structure or activity / axo-dendritic transport / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / mating behavior / regulation of spontaneous synaptic transmission / ciliary rootlet / Golgi-associated vesicle / PTB domain binding / Lysosome Vesicle Biogenesis / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / signaling receptor activator activity / dendrite development / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / presynaptic active zone / positive regulation of protein metabolic process / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / neuromuscular process controlling balance / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / transition metal ion binding / intracellular copper ion homeostasis / regulation of presynapse assembly / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / forebrain development / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / protein serine/threonine kinase binding / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / ionotropic glutamate receptor signaling pathway / response to interleukin-1 / positive regulation of mitotic cell cycle / cholesterol metabolic process / axonogenesis / positive regulation of calcium-mediated signaling / platelet alpha granule lumen / adult locomotory behavior / positive regulation of glycolytic process / dendritic shaft / central nervous system development / learning / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / endosome lumen / locomotory behavior / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / synapse organization / TAK1-dependent IKK and NF-kappa-B activation / positive regulation of non-canonical NF-kappaB signal transduction / visual learning / neuromuscular junction / recycling endosome / positive regulation of interleukin-6 production / Golgi lumen / cognition / neuron cellular homeostasis / positive regulation of inflammatory response / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / neuron projection development / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / apical part of cell / synaptic vesicle / cell-cell junction / Platelet degranulation
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 / Resolution: 1.402 Å
AuthorsGriner SL / Sawaya MR
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01 AG029430 United States
CitationJournal: Elife / Year: 2019
Title: Structure-based inhibitors of amyloid beta core suggest a common interface with tau.
Authors: Sarah L Griner / Paul Seidler / Jeannette Bowler / Kevin A Murray / Tianxiao Peter Yang / Shruti Sahay / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Stephan Philipp / Justyna Sosna ...Authors: Sarah L Griner / Paul Seidler / Jeannette Bowler / Kevin A Murray / Tianxiao Peter Yang / Shruti Sahay / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Stephan Philipp / Justyna Sosna / Charles G Glabe / Tamir Gonen / David S Eisenberg /
Abstract: Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ...Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline.
History
DepositionFeb 28, 2019-
Header (metadata) releaseMar 20, 2019-
Map releaseOct 30, 2019-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.7
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.7
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6o4j
  • Surface level: 0.7
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0619.png

Downloads & links

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Map

FileDownload / File: emd_0619.map.gz / Format: CCP4 / Size: 304.7 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationAmyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)X (Row.)Y (Col.)
0.35 Å/pix.
x 36 pix.
= 12.76 Å		0.39 Å/pix.
x 30 pix.
= 11.67 Å		0.36 Å/pix.
x 72 pix.
= 51.91 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX: 0.389 Å / Y: 0.36049 Å / Z: 0.35444 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.7 / Movie #1: 0.7
Minimum - Maximum-1.8594286 - 3.3643832
Average (Standard dev.)0.000000000266055 (±0.47364908)
SymmetrySpace group: 4
Details

EMDB XML:

Map geometry
Axis orderYXZ
Origin000
Dimensions307236
Spacing3014436
CellA: 11.67 Å / B: 51.91 Å / C: 12.76 Å
α: 90.0 ° / β: 114.18 ° / γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.3890.360486111111110.35444444444444
M x/y/z3014436
origin x/y/z0.0000.0000.000
length x/y/z11.67051.91012.760
α/β/γ90.000114.18090.000
start NX/NY/NZ000
NX/NY/NZ307236
MAP C/R/S213
start NC/NR/NS000
NC/NR/NS723036
D min/max/mean-1.8593.3640.000

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Supplemental data

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Sample components

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Entire : Fibrils of Amyloid Beta segment 16-26

EntireName: Fibrils of Amyloid Beta segment 16-26
Components
  • Complex: Fibrils of Amyloid Beta segment 16-26
    • Protein or peptide: Amyloid-beta precursor protein

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Supramolecule #1: Fibrils of Amyloid Beta segment 16-26

SupramoleculeName: Fibrils of Amyloid Beta segment 16-26 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Amyloid-beta precursor protein

MacromoleculeName: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.235432 KDa
SequenceString:
(ACE)KLVFFAENV GS(NH2)

UniProtKB: Amyloid-beta precursor protein

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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

Concentration7.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
200.0 mMMgCl2magnesium formate
10.0 %C2H6OSDMSO
100.0 mMC4H11NO3Tris Base
15.0 %C3H8Oisopropanol
GridSupport film - Material: CARBON / Support film - topology: HOLEY / Details: unspecified
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV
Detailsnanocrystals
Crystal formationInstrument: microcentrifuge tube / Atmosphere: air / Temperature: 310.0 K / Time: 4.0 DAY

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Electron microscopy

MicroscopeFEI TECNAI F20
Image recordingFilm or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Digitization - Dimensions - Width: 2048 pixel / Digitization - Dimensions - Height: 2048 pixel / Number diffraction images: 1331 / Average electron dose: 0.03 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Camera length: 1840 mm
Sample stageSpecimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 1.402 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES
Crystallography statisticsNumber intensities measured: 47598 / Number structure factors: 2355 / Fourier space coverage: 85.4 / R sym: 0.24 / R merge: 0.24 / Overall phase error: 0 / Overall phase residual: 0.01 / Phase error rejection criteria: 0 / High resolution: 1.4 Å / Shell - Shell ID: 1 / Shell - High resolution: 1.4 Å / Shell - Low resolution: 1.44 Å / Shell - Number structure factors: 163 / Shell - Phase residual: 0.01 / Shell - Fourier space coverage: 78 / Shell - Multiplicity: 12.1

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Atomic model buiding 1

Initial modelPDB ID:

2y2a


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: RECIPROCAL / Protocol: OTHER / Target criteria: Maximum likelihood
Output model

PDB-6o4j:
Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation

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