|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) intracellular domain signature. / Amyloidogenic glycoprotein / Amyloidogenic glycoprotein, extracellular domain conserved site / Beta-amyloid precursor protein C-terminal / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, amyloid-beta peptide / PH-like domain superfamily / Amyloidogenic glycoprotein, copper-binding ...Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein / Amyloidogenic glycoprotein, extracellular domain conserved site / Beta-amyloid precursor protein C-terminal / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, amyloid-beta peptide / PH-like domain superfamily / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, extracellular / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor Kunitz domain / Platelet degranulation / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / Formyl peptide receptors bind formyl peptides and many other ligands / ECM proteoglycans / Lysosome Vesicle Biogenesis / Pancreatic trypsin inhibitor (Kunitz) family profile. / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / G alpha (q) signalling events / Amyloidogenic glycoprotein, intracellular domain, conserved site / G alpha (i) signalling events / Amyloidogenic glycoprotein, E2 domain / Amyloid A4 N-terminal heparin-binding / Amyloid fiber formation / Beta-amyloid precursor protein C-terminus / Copper-binding of amyloid precursor, CuBD / E2 domain of amyloid precursor protein / Pancreatic trypsin inhibitor (Kunitz) family signature. / Amyloid beta A4 protein / Beta-amyloid peptide (beta-APP) / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor Kunitz domain superfamily / TRAF6 mediated NF-kB activation / Post-translational protein phosphorylation / Amyloidogenic glycoprotein, copper-binding domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / E2 domain superfamily / positive regulation of G protein-coupled receptor internalization / amyloid-beta complex / amylin binding / regulation of acetylcholine-gated cation channel activity / positive regulation of protein import / positive regulation of cellular response to thapsigargin / positive regulation of cellular response to tunicamycin / heparan sulfate binding / receptor activator activity / positive regulation of 1-phosphatidylinositol-3-kinase activity / positive regulation of response to endoplasmic reticulum stress / 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 / microglia development / lipoprotein particle / synaptic growth at neuromuscular junction / positive regulation of oxidative stress-induced neuron death / growth cone lamellipodium / negative regulation of mitochondrion organization / regulation of synapse structure or activity / mating behavior / regulation of amyloid fibril formation / astrocyte projection / smooth endoplasmic reticulum calcium ion homeostasis / cellular process / protein trimerization / regulation of epidermal growth factor-activated receptor activity / tumor necrosis factor production / growth cone filopodium / regulation of spontaneous synaptic transmission / axon midline choice point recognition / axo-dendritic transport / astrocyte activation involved in immune response / positive regulation of astrocyte activation / positive regulation of amyloid fibril formation / intermediate-density lipoprotein particle / PTB domain binding / suckling behavior / modulation of excitatory postsynaptic potential / activation of MAPKKK activity / positive regulation of amyloid-beta formation / positive regulation of G protein-coupled receptor signaling pathway / neuron remodeling / ciliary rootlet / positive regulation of microglial cell activation / high-density lipoprotein particle / peptidase activator activity / lipoprotein metabolic process / positive regulation of cell activation / main axon / dendrite development / positive regulation of protein metabolic process / negative regulation of protein localization to nucleus / heparan sulfate proteoglycan binding|
Function and homology information
|Source||Homo sapiens (human)|
|Method||electron crystallography / cryo EM|
|Authors||Krotee P / Griner SL / Sawaya MR / Cascio D / Rodriguez JA / Shi D / Philipp S / Murray K / Saelices L / Lee J / Seidler P / Glabe CG / Jiang L / Gonen T / Eisenberg DS|
|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 / Recombinant expression: No|
|Mass||Theoretical: 1.029213 kDa|
-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
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