|Entry||Database: PDB / ID: 5oqv|
|Title||Near-atomic resolution fibril structure of complete amyloid-beta(1-42) by cryo-EM|
|Components||Amyloid beta A4 protein|
|Keywords||PROTEIN FIBRIL / amyloid / fibril / aggregation / Alzheimer's disease / Protein fibril|
|Function / homology||RIP-mediated NFkB activation via ZBP1 / Proteinase inhibitor I2, Kunitz, conserved site / The NLRP3 inflammasome / Amyloidogenic glycoprotein, copper-binding domain superfamily / G alpha (q) signalling events / Amyloidogenic glycoprotein, heparin-binding domain superfamily / G alpha (i) signalling events / E2 domain superfamily / Amyloid beta A4 protein / Lysosome Vesicle Biogenesis ...RIP-mediated NFkB activation via ZBP1 / Proteinase inhibitor I2, Kunitz, conserved site / The NLRP3 inflammasome / Amyloidogenic glycoprotein, copper-binding domain superfamily / G alpha (q) signalling events / Amyloidogenic glycoprotein, heparin-binding domain superfamily / G alpha (i) signalling events / E2 domain superfamily / Amyloid beta A4 protein / Lysosome Vesicle Biogenesis / Amyloidogenic glycoprotein, E2 domain / Amyloidogenic glycoprotein, intracellular domain, conserved site / Pancreatic trypsin inhibitor Kunitz domain superfamily / DEx/H-box helicases activate type I IFN and inflammatory cytokines production / Amyloidogenic glycoprotein, extracellular domain conserved site / Formyl peptide receptors bind formyl peptides and many other ligands / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, heparin-binding / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / Amyloidogenic glycoprotein, amyloid-beta peptide / Pancreatic trypsin inhibitor Kunitz domain / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein / Advanced glycosylation endproduct receptor signaling / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / PH-like domain superfamily / Copper-binding of amyloid precursor, CuBD / Platelet degranulation / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Pancreatic trypsin inhibitor (Kunitz) family profile. / ECM proteoglycans / Amyloidogenic glycoprotein intracellular domain signature. / Amyloid fiber formation / Amyloidogenic glycoprotein extracellular domain signature. / Pancreatic trypsin inhibitor (Kunitz) family signature. / E2 domain of amyloid precursor protein / TRAF6 mediated NF-kB activation / Post-translational protein phosphorylation / beta-amyloid precursor protein C-terminus / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / Beta-amyloid peptide (beta-APP) / Amyloid A4 N-terminal heparin-binding / Kunitz/Bovine pancreatic trypsin inhibitor domain / Amyloidogenic glycoprotein, copper-binding / positive regulation of cellular response to tunicamycin / positive regulation of G-protein coupled receptor internalization / positive regulation of protein import / regulation of acetylcholine-gated cation channel activity / amylin binding / positive regulation of cellular response to thapsigargin / positive regulation of 1-phosphatidylinositol-3-kinase activity / heparan sulfate binding / receptor activator activity / positive regulation of response to endoplasmic reticulum stress / regulation of response to calcium ion / acetylcholine receptor activator activity / regulation of dendritic spine maintenance / endosome to plasma membrane transport vesicle / collateral sprouting in absence of injury / cellular response to norepinephrine stimulus / lipoprotein particle / positive regulation of oxidative stress-induced neuron death / synaptic growth at neuromuscular junction / microglia development / growth cone lamellipodium / regulation of synapse structure or activity / negative regulation of mitochondrion organization / mating behavior / regulation of amyloid fibril formation / astrocyte projection / smooth endoplasmic reticulum calcium ion homeostasis / protein trimerization / regulation of epidermal growth factor-activated receptor activity / growth cone filopodium / regulation of spontaneous synaptic transmission / axo-dendritic transport / cellular process / tumor necrosis factor production / axon midline choice point recognition / astrocyte activation involved in immune response / positive regulation of astrocyte activation / intermediate-density lipoprotein particle / positive regulation of amyloid fibril formation / suckling behavior / PTB domain binding / go:0030816: / modulation of excitatory postsynaptic potential / positive regulation of microglial cell activation / neuron remodeling / amyloid-beta complex / acetylcholine receptor binding / positive regulation of G-protein coupled receptor protein signaling pathway / main axon / activation of MAPKKK activity / positive regulation of amyloid-beta formation / ciliary rootlet / positive regulation of cell activation / high-density lipoprotein particle / lipoprotein metabolic process / peptidase activator activity|
Function and homology information
|Specimen source||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / helical reconstruction / cryo EM / 4 Å resolution|
|Authors||Gremer, L. / Schoelzel, D. / Schenk, C. / Reinartz, E. / Labahn, J. / Ravelli, R. / Tusche, M. / Lopez-Iglesias, C. / Hoyer, W. / Heise, H. / Willbold, D. / Schroeder, G.F.|
|Citation||Journal: Science / Year: 2017|
Title: Fibril structure of amyloid-β(1-42) by cryo-electron microscopy.
Authors: Lothar Gremer / Daniel Schölzel / Carla Schenk / Elke Reinartz / Jörg Labahn / Raimond B G Ravelli / Markus Tusche / Carmen Lopez-Iglesias / Wolfgang Hoyer / Henrike Heise / Dieter Willbold / Gunnar F Schröder
Abstract: Amyloids are implicated in neurodegenerative diseases. Fibrillar aggregates of the amyloid-β protein (Aβ) are the main component of the senile plaques found in brains of Alzheimer's disease ...Amyloids are implicated in neurodegenerative diseases. Fibrillar aggregates of the amyloid-β protein (Aβ) are the main component of the senile plaques found in brains of Alzheimer's disease patients. We present the structure of an Aβ(1-42) fibril composed of two intertwined protofilaments determined by cryo-electron microscopy (cryo-EM) to 4.0-angstrom resolution, complemented by solid-state nuclear magnetic resonance experiments. The backbone of all 42 residues and nearly all side chains are well resolved in the EM density map, including the entire N terminus, which is part of the cross-β structure resulting in an overall "LS"-shaped topology of individual subunits. The dimer interface protects the hydrophobic C termini from the solvent. The characteristic staggering of the nonplanar subunits results in markedly different fibril ends, termed "groove" and "ridge," leading to different binding pathways on both fibril ends, which has implications for fibril growth.
SummaryFull reportAbout validation report
|Date||Deposition: Aug 14, 2017 / Release: Sep 13, 2017|
|Structure viewer||Molecule: |
Downloads & links
A: Amyloid beta A4 protein
B: Amyloid beta A4 protein
C: Amyloid beta A4 protein
D: Amyloid beta A4 protein
E: Amyloid beta A4 protein
F: Amyloid beta A4 protein
G: Amyloid beta A4 protein
H: Amyloid beta A4 protein
I: Amyloid beta A4 protein
Mass: 4520.087 Da / Num. of mol.: 9 / Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Production host: Escherichia coli (E. coli) / References: UniProt: P05067
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: FILAMENT / Reconstruction method: helical reconstruction|
|Component||Name: Beta-amyloid protein 42 fibrilsAmyloid beta / Type: COMPLEX / Entity ID: 1 / Source: RECOMBINANT|
|Molecular weight||Experimental value: NO|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Escherichia coli (E. coli)|
|Buffer solution||Details: in water / pH: 2|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: GOLD / Grid mesh size: 300 / Grid type: UltrAuFoil R 1.2/1.3 Quantifoil|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE|
Details: 2.5 microL sample was applied to the grid, blotted for 2.5 s before plunging.
-Electron microscopy imaging
Model: Talos Arctica / Image courtesy: FEI Company
|Microscopy||Microscope model: FEI TECNAI ARCTICA|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 110000 / Cs: 2.7 mm|
|Image recording||Average exposure time: 2 sec. / Electron dose: 24 e/Å2 / Detector mode: INTEGRATING / Film or detector model: FEI FALCON III (4k x 4k) / Number of grids imaged: 1 / Number of real images: 2026|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Helical symmerty||Angular rotation/subunit: -179.275 deg. / Axial rise/subunit: 2.335 Å / Axial symmetry: C1|
|3D reconstruction||Resolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 127765|
Details: For the even/odd test, the fibrils were split after the final reconstruction (no gold-standard). These two half sets were then refined further independently for another 12 iterations.
Number of class averages: 1 / Symmetry type: HELICAL
|Atomic model building||Ref protocol: AB INITIO MODEL / Ref space: REAL / Target criteria: Cross-correlation coefficient|
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