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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-0619 | |||||||||
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Title | Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation | |||||||||
![]() | Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation | |||||||||
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![]() | amyloid / PROTEIN FIBRIL | |||||||||
Function / homology | ![]() regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of Wnt signaling pathway / regulation of synapse structure or activity / 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 Wnt signaling pathway / regulation of synapse structure or activity / 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 / axonogenesis / extracellular matrix organization / positive regulation of peptidyl-threonine phosphorylation / platelet alpha granule lumen / trans-Golgi network membrane / 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 / microglial cell activation / regulation of long-term neuronal synaptic plasticity / 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 / positive regulation of interleukin-6 production / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | electron crystallography / cryo EM / Resolution: 1.402 Å | |||||||||
![]() | Griner SL / Sawaya MR | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 280.9 KB | ![]() | |
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Header (meta data) | ![]() ![]() | 12.9 KB 12.9 KB | Display Display | ![]() |
Images | ![]() | 598.5 KB | ||
Filedesc metadata | ![]() | 5.4 KB | ||
Filedesc structureFactors | ![]() | 49.4 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 379.1 KB | Display | ![]() |
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Full document | ![]() | 378.7 KB | Display | |
Data in XML | ![]() | 4.2 KB | Display | |
Data in CIF | ![]() | 4.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6o4jMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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
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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: ![]() |
-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: ![]() |
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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![]() | electron crystallography |
Aggregation state | 3D array |
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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 |
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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: ![]() |
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 |
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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 |