+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-0619 | |||||||||
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Title | Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation | |||||||||
Map data | Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation | |||||||||
Sample |
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Keywords | amyloid / 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 / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / 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 / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / positive regulation of G2/M transition of mitotic cell cycle / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / dendrite development / presynaptic active zone / modulation of excitatory postsynaptic potential / regulation of peptidyl-tyrosine phosphorylation / 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 / ECM proteoglycans / intracellular copper ion homeostasis / smooth endoplasmic reticulum / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / protein serine/threonine kinase binding / positive regulation of chemokine production / clathrin-coated pit / forebrain development / Notch signaling pathway / neuron projection maintenance / positive regulation of protein metabolic process / positive regulation of calcium-mediated signaling / astrocyte activation / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / response to interleukin-1 / cholesterol metabolic process / positive regulation of mitotic cell cycle / extracellular matrix organization / adult locomotory behavior / axonogenesis / platelet alpha granule lumen / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / positive regulation of interleukin-1 beta production / learning / dendritic shaft / positive regulation of long-term synaptic potentiation / Mitochondrial protein degradation / central nervous system development / locomotory behavior / endosome lumen / positive regulation of JNK cascade / Post-translational protein phosphorylation / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / TAK1-dependent IKK and NF-kappa-B activation / visual learning / neuromuscular junction / positive regulation of non-canonical NF-kappaB signal transduction / recycling endosome / cognition / G2/M transition of mitotic cell cycle / Golgi lumen / positive regulation of inflammatory response / neuron cellular homeostasis / positive regulation of interleukin-6 production / cellular response to amyloid-beta / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / serine-type endopeptidase inhibitor activity / positive regulation of peptidyl-serine phosphorylation / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | electron crystallography / cryo EM / Resolution: 1.402 Å | |||||||||
Authors | Griner SL / Sawaya MR | |||||||||
Funding support | United States, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_0619.map.gz | 280.9 KB | EMDB map data format | |
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Header (meta data) | emd-0619-v30.xml emd-0619.xml | 12.9 KB 12.9 KB | Display Display | EMDB header |
Images | emd_0619.png | 598.5 KB | ||
Filedesc metadata | emd-0619.cif.gz | 5.4 KB | ||
Filedesc structureFactors | emd_0619_sf.cif.gz | 49.4 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-0619 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-0619 | HTTPS FTP |
-Validation report
Summary document | emd_0619_validation.pdf.gz | 379.1 KB | Display | EMDB validaton report |
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Full document | emd_0619_full_validation.pdf.gz | 378.7 KB | Display | |
Data in XML | emd_0619_validation.xml.gz | 4.2 KB | Display | |
Data in CIF | emd_0619_validation.cif.gz | 4.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0619 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0619 | HTTPS FTP |
-Related structure data
Related structure data | 6o4jMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_0619.map.gz / Format: CCP4 / Size: 304.7 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X: 0.389 Å / Y: 0.36049 Å / Z: 0.35444 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : Fibrils of Amyloid Beta segment 16-26
Entire | Name: Fibrils of Amyloid Beta segment 16-26 |
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Components |
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-Supramolecule #1: Fibrils of Amyloid Beta segment 16-26
Supramolecule | Name: Fibrils of Amyloid Beta segment 16-26 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Amyloid-beta precursor protein
Macromolecule | Name: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 1.235432 KDa |
Sequence | String: (ACE)KLVFFAENV GS(NH2) UniProtKB: Amyloid-beta precursor protein |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | electron crystallography |
Aggregation state | 3D array |
-Sample preparation
Concentration | 7.5 mg/mL | |||||||||||||||
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Buffer | pH: 8 Component:
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Grid | Support film - Material: CARBON / Support film - topology: HOLEY / Details: unspecified | |||||||||||||||
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV | |||||||||||||||
Details | nanocrystals | |||||||||||||||
Crystal formation | Instrument: microcentrifuge tube / Atmosphere: air / Temperature: 310.0 K / Time: 4.0 DAY |
-Electron microscopy
Microscope | FEI TECNAI F20 |
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Image recording | Film 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 beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Camera length: 1840 mm |
Sample stage | Specimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Tecnai F20 / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 1.402 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES |
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Crystallography statistics | Number 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 |