|Entry||Database: EMDB / ID: 8720|
|Title||VGSNKGAIIGL from Amyloid Beta determined by MicroED|
|Map data||VGSNKGAIIGL from Amyloid Beta|
|Sample||Fibrils of Amyloid Beta segment 24-34:|
Amyloid beta A4 protein / ligand
|Function / homology||Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Beta-amyloid precursor protein C-terminal / The NLRP3 inflammasome / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / Amyloidogenic glycoprotein, E2 domain / Proteinase inhibitor I2, Kunitz, conserved site / Platelet degranulation / Amyloidogenic glycoprotein, intracellular domain, conserved site / Amyloidogenic glycoprotein, extracellular domain conserved site / ECM proteoglycans ...Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Beta-amyloid precursor protein C-terminal / The NLRP3 inflammasome / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / Amyloidogenic glycoprotein, E2 domain / Proteinase inhibitor I2, Kunitz, conserved site / Platelet degranulation / Amyloidogenic glycoprotein, intracellular domain, conserved site / Amyloidogenic glycoprotein, extracellular domain conserved site / ECM proteoglycans / Amyloidogenic glycoprotein, heparin-binding / E2 domain superfamily / Amyloidogenic glycoprotein, amyloid-beta peptide / PH-like domain superfamily / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein / Amyloidogenic glycoprotein, extracellular / Pancreatic trypsin inhibitor Kunitz domain / G alpha (q) signalling events / G alpha (i) signalling events / Formyl peptide receptors bind formyl peptides and many other ligands / Amyloid beta A4 protein / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family signature. / Pancreatic trypsin inhibitor (Kunitz) family profile. / Amyloid precursor protein (APP) E1 domain profile. / E2 domain of amyloid precursor protein / Copper-binding of amyloid precursor, CuBD / Amyloid fiber formation / Beta-amyloid precursor protein C-terminus / Beta-amyloid peptide (beta-APP) / Amyloid A4 N-terminal heparin-binding / Amyloid precursor protein (APP) E2 domain profile. / TRAF6 mediated NF-kB activation / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / Amyloidogenic glycoprotein, copper-binding domain superfamily / Pancreatic trypsin inhibitor Kunitz domain superfamily / Post-translational protein phosphorylation / Advanced glycosylation endproduct receptor signaling / Lysosome Vesicle Biogenesis / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / positive regulation of cellular response to thapsigargin / positive regulation of protein import / amyloid-beta complex / amylin binding / regulation of acetylcholine-gated cation channel activity / positive regulation of G protein-coupled receptor internalization / positive regulation of cellular response to tunicamycin / heparan sulfate binding / receptor activator activity / positive regulation of response to endoplasmic reticulum stress / positive regulation of 1-phosphatidylinositol-3-kinase activity / regulation of response to calcium ion / endosome to plasma membrane transport vesicle / acetylcholine receptor activator activity / collateral sprouting in absence of injury / regulation of dendritic spine maintenance / cellular response to norepinephrine stimulus / lipoprotein particle / positive regulation of oxidative stress-induced neuron death / microglia development / growth cone lamellipodium / negative regulation of mitochondrion organization / mating behavior / regulation of amyloid fibril formation / cellular process / protein trimerization / growth cone filopodium / regulation of epidermal growth factor-activated receptor activity / smooth endoplasmic reticulum calcium ion homeostasis / regulation of spontaneous synaptic transmission / axon midline choice point recognition / positive regulation of astrocyte activation / astrocyte projection / astrocyte activation involved in immune response / tumor necrosis factor production / synaptic growth at neuromuscular junction / regulation of synapse structure or activity / positive regulation of amyloid fibril formation / intermediate-density lipoprotein particle / PTB domain binding / modulation of excitatory postsynaptic potential / suckling behavior / Golgi-associated vesicle / positive regulation of G protein-coupled receptor signaling pathway / neuron remodeling / activation of MAPKKK activity / positive regulation of amyloid-beta formation / ciliary rootlet / peptidase activator activity / high-density lipoprotein particle / positive regulation of cell activation / main axon / positive regulation of protein metabolic process / negative regulation of protein localization to nucleus / positive regulation of microglial cell activation / dendrite development|
Function and homology information
|Source||Homo sapiens (human)|
|Method||electron crystallography / cryo EM|
|Authors||Rodriguez JA / Sawaya MR / Cascio D / Eisenberg DS / Griner SL / Gonen T|
|Citation||Journal: 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 / 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.
|Validation Report||PDB-ID: 5vos|
SummaryFull reportAbout validation report
|Date||Deposition: May 3, 2017 / Header (metadata) release: Jul 19, 2017 / Map release: Jan 3, 2018 / Last update: Jun 6, 2018|
|Structure viewer||EM map: |
Downloads & links
|File||emd_8720.map.gz (map file in CCP4 format, 217 KB)|
|Projections & slices|
Images are generated by Spider.
(generated in cubic-lattice coordinate)
|Voxel size||X: 0.4675 Å / Y: 0.3916 Å / Z: 0.4648 Å|
CCP4 map header:
-Entire Fibrils of Amyloid Beta segment 24-34
|Entire||Name: Fibrils of Amyloid Beta segment 24-34 / Number of components: 3|
-Component #1: protein, Fibrils of Amyloid Beta segment 24-34
|Protein||Name: Fibrils of Amyloid Beta segment 24-34 / Recombinant expression: No|
|Source||Species: Homo sapiens (human)|
-Component #2: protein, Amyloid beta A4 protein
|Protein||Name: Amyloid beta A4 protein / Number of Copies: 1 / Recombinant expression: No|
|Mass||Theoretical: 1.029213 kDa|
|Source||Species: Homo sapiens (human)|
-Component #3: ligand, water
|Ligand||Name: water / Number of Copies: 1 / Recombinant expression: No|
|Mass||Theoretical: 1.801505 MDa|
|Specimen||Specimen state: 3D array / Method: cryo EM|
|Crystal parameters||Space group: P 21 / A: 18.78 Å / B: 4.73 Å / C: 33.47 Å / Alpha: 90 deg. / Beta: 100.017 deg. / Gamma: 90 deg.|
|Crystal grow details||shaking|
|Sample solution||Specimen conc.: 7.5 mg/ml / pH: 4|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Tecnai F20 / Image courtesy: FEI Company
|Imaging||Microscope: FEI TECNAI F20|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Electron dose: 0.03 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Imaging mode: DIFFRACTION|
|Specimen Holder||Model: GATAN LIQUID NITROGEN|
|Camera||Detector: TVIPS TEMCAM-F416 (4k x 4k)|
|Processing||Method: electron crystallography|
|3D reconstruction||Resolution method: DIFFRACTION PATTERN/LAYERLINES|
-Atomic model buiding
|Modeling #1||Target criteria: Maximum likelihood / Refinement space: RECIPROCAL|
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