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- EMDB-8720: VGSNKGAIIGL from Amyloid Beta determined by MicroED -

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Basic information

Entry
Database: EMDB / ID: EMD-8720
TitleVGSNKGAIIGL from Amyloid Beta determined by MicroED
Map dataVGSNKGAIIGL from Amyloid Beta
Sample
  • Complex: Fibrils of Amyloid Beta segment 24-34
    • Protein or peptide: Amyloid beta A4 protein
  • Ligand: water
KeywordsAmyloid / steric zipper / PROTEIN FIBRIL
Function / homology
Function and homology information


regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity ...regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / positive regulation of amyloid fibril formation / neuron remodeling / : / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / suckling behavior / nuclear envelope lumen / dendrite development / COPII-coated ER to Golgi transport vesicle / presynaptic active zone / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / regulation of presynapse assembly / transition metal ion binding / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / negative regulation of neuron differentiation / intracellular copper ion homeostasis / ECM proteoglycans / smooth endoplasmic reticulum / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / protein serine/threonine kinase binding / positive regulation of chemokine production / clathrin-coated pit / regulation of peptidyl-tyrosine phosphorylation / forebrain development / Notch signaling pathway / Mitochondrial protein degradation / neuron projection maintenance / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / cholesterol metabolic process / response to interleukin-1 / positive regulation of mitotic cell cycle / adult locomotory behavior / extracellular matrix organization / axonogenesis / platelet alpha granule lumen / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / dendritic shaft / learning / positive regulation of interleukin-1 beta production / locomotory behavior / positive regulation of long-term synaptic potentiation / central nervous system development / endosome lumen / astrocyte activation / positive regulation of JNK cascade / Post-translational protein phosphorylation / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation / visual learning / serine-type endopeptidase inhibitor activity / neuromuscular junction / recycling endosome / cognition / neuron cellular homeostasis / Golgi lumen / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / endocytosis / cellular response to amyloid-beta / G2/M transition of mitotic cell cycle / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle
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 A4 protein / Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodelectron crystallography / cryo EM
AuthorsRodriguez JA / Sawaya MR / Cascio D / Eisenberg DS / Griner SL / Gonen T
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: J Biol Chem / Year: 2018
Title: Common fibrillar spines of amyloid-β and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors.
Authors: Pascal Krotee / Sarah L Griner / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Dan Shi / Stephan Philipp / Kevin Murray / Lorena Saelices / Ji Lee / Paul Seidler / Charles G Glabe / ...Authors: Pascal Krotee / Sarah L Griner / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Dan Shi / Stephan Philipp / Kevin Murray / Lorena Saelices / Ji Lee / Paul Seidler / Charles G Glabe / Lin Jiang / Tamir Gonen / David S Eisenberg /
Abstract: Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregate to form amyloid fibrils that deposit in tissues and are associated with Alzheimer's disease (AD) and type II diabetes (T2D), ...Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregate to form amyloid fibrils that deposit in tissues and are associated with Alzheimer's disease (AD) and type II diabetes (T2D), respectively. Individuals with T2D have an increased risk of developing AD, and conversely, AD patients have an increased risk of developing T2D. Evidence suggests that this link between AD and T2D might originate from a structural similarity between aggregates of Aβ and hIAPP. Using the cryoEM method microelectron diffraction, we determined the atomic structures of 11-residue segments from both Aβ and hIAPP, termed Aβ(24-34) WT and hIAPP(19-29) S20G, with 64% sequence similarity. We observed a high degree of structural similarity between their backbone atoms (0.96-Å root mean square deviation). Moreover, fibrils of these segments induced amyloid formation through self- and cross-seeding. Furthermore, inhibitors designed for one segment showed cross-efficacy for full-length Aβ and hIAPP and reduced cytotoxicity of both proteins, although by apparently blocking different cytotoxic mechanisms. The similarity of the atomic structures of Aβ(24-34) WT and hIAPP(19-29) S20G offers a molecular model for cross-seeding between Aβ and hIAPP.
History
DepositionMay 3, 2017-
Header (metadata) releaseJul 19, 2017-
Map releaseJan 3, 2018-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5vos
  • Surface level: 0.3
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8720.png

Downloads & links

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Map

FileDownload / File: emd_8720.map.gz / Format: CCP4 / Size: 211.9 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationVGSNKGAIIGL from Amyloid Beta
Voxel sizeX: 0.4675 Å / Y: 0.3916 Å / Z: 0.4648 Å
Density
Contour LevelBy EMDB: 0.3 / Movie #1: 0.3
Minimum - Maximum-0.61619514 - 1.0237845
Average (Standard dev.)0.0034368462 (±0.20555635)
SymmetrySpace group: 4
Details

EMDB XML:

Map geometry
Axis orderZXY
Origin-1265-8
Dimensions537314
Spacing401272
CellA: 18.7 Å / B: 4.6992 Å / C: 33.4656 Å
α: 90.0 ° / β: 100.017 ° / γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.46750.391583333333330.46480555555556
M x/y/z401272
origin x/y/z0.0000.0000.000
length x/y/z18.7004.69933.466
α/β/γ90.000100.01790.000
start NX/NY/NZ-12-865
NX/NY/NZ531473
MAP C/R/S312
start NC/NR/NS65-12-8
NC/NR/NS735314
D min/max/mean-0.6161.0240.003

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Supplemental data

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Sample components

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Entire : Fibrils of Amyloid Beta segment 24-34

EntireName: Fibrils of Amyloid Beta segment 24-34
Components
  • Complex: Fibrils of Amyloid Beta segment 24-34
    • Protein or peptide: Amyloid beta A4 protein
  • Ligand: water

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Supramolecule #1: Fibrils of Amyloid Beta segment 24-34

SupramoleculeName: Fibrils of Amyloid Beta segment 24-34 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 1.029213 KDa
SequenceString:
VGSNKGAIIG L

UniProtKB: Amyloid-beta A4 protein

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Macromolecule #2: water

MacromoleculeName: water / type: ligand / ID: 2 / Number of copies: 1 / 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

Concentration7.5 mg/mL
BufferpH: 4 / Component:
ConcentrationName
25.0 mMcitric acid
5.0 %DMSO
GridModel: Quantifoil / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV
Detailsnanocrystals
Crystal formationInstrument: microcentrifuge tube / Atmosphere: air / Temperature: 310.0 K / Time: 2.0 DAY / Details: shaking

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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: 471 / 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 method: DIFFRACTION PATTERN/LAYERLINES
Molecular replacementSoftware - Name: phaser
Merging software listSoftware - Name: XSCALE (ver. Jun 17, 2015)
Crystallography statisticsNumber intensities measured: 5843 / Number structure factors: 1129 / Fourier space coverage: 85.5 / R sym: 0.222 / R merge: 0.222 / Overall phase error: 0 / Overall phase residual: 0.01 / Phase error rejection criteria: 0 / High resolution: 1.42 Å / Shell - Shell ID: 1 / Shell - High resolution: 1.42 Å / Shell - Low resolution: 1.49 Å / Shell - Number structure factors: 84 / Shell - Phase residual: 0.01 / Shell - Fourier space coverage: 47.5 / Shell - Multiplicity: 2.6

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: OTHER / Target criteria: Maximum likelihood
Output model

PDB-5vos:
VGSNKGAIIGL from Amyloid Beta determined by MicroED

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