|Entry||Database: PDB / ID: 6w0o|
|Title||Amyloid-beta(1-40) fibril derived from Alzheimer's disease cortical tissue|
|Components||Amyloid-beta precursor protein|
|Keywords||PROTEIN FIBRIL / amyloid-beta / Alzheimer's disease|
|Function / homology|
Function and homology information
amylin binding / acetylcholine receptor activator activity / positive regulation of protein import / regulation of acetylcholine-gated cation channel activity / positive regulation of G protein-coupled receptor internalization / positive regulation of cellular response to thapsigargin / positive regulation of cellular response to tunicamycin / amyloid-beta complex / regulation of response to calcium ion / signaling receptor activator activity ...amylin binding / acetylcholine receptor activator activity / positive regulation of protein import / regulation of acetylcholine-gated cation channel activity / positive regulation of G protein-coupled receptor internalization / positive regulation of cellular response to thapsigargin / positive regulation of cellular response to tunicamycin / amyloid-beta complex / regulation of response to calcium ion / signaling receptor activator activity / positive regulation of response to endoplasmic reticulum stress / growth cone lamellipodium / positive regulation of 1-phosphatidylinositol-3-kinase activity / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / endosome to plasma membrane transport vesicle / microglia development / regulation of epidermal growth factor-activated receptor activity / regulation of dendritic spine maintenance / protein trimerization / positive regulation of endothelin production / negative regulation of blood circulation / mating behavior / lipoprotein particle / regulation of amyloid-beta clearance / positive regulation of oxidative stress-induced neuron death / smooth endoplasmic reticulum calcium ion homeostasis / negative regulation of mitochondrion organization / regulation of amyloid fibril formation / regulation of spontaneous synaptic transmission / tumor necrosis factor production / axon midline choice point recognition / synaptic growth at neuromuscular junction / astrocyte activation involved in immune response / cellular process / regulation of synapse structure or activity / positive regulation of amyloid fibril formation / modulation of excitatory postsynaptic potential / PTB domain binding / intermediate-density lipoprotein particle / astrocyte projection / positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process / Golgi-associated vesicle / ciliary rootlet / peptidase activator activity / positive regulation of G protein-coupled receptor signaling pathway / axo-dendritic transport / activation of MAPKKK activity / positive regulation of protein metabolic process / positive regulation of cell activation / main axon / RAGE receptor binding / neuron remodeling / negative regulation of protein localization to nucleus / high-density lipoprotein particle / positive regulation of T cell migration / frizzled binding / response to yeast / heparan sulfate binding / heparan sulfate proteoglycan binding / lipoprotein metabolic process / dendrite development / COPII-coated ER to Golgi transport vesicle / nuclear envelope lumen / suckling behavior / regulation of presynapse assembly / positive regulation of membrane protein ectodomain proteolysis / positive regulation of chemokine production => GO:0032722 / positive regulation of protein kinase A signaling / negative regulation of pri-miRNA transcription by RNA polymerase II / mRNA polyadenylation / positive regulation of monocyte chemotaxis / smooth endoplasmic reticulum / acetylcholine receptor binding / low-density lipoprotein particle receptor binding / antifungal humoral response / negative regulation of long-term synaptic potentiation / cellular copper ion homeostasis / growth factor receptor binding / neuromuscular process controlling balance / positive regulation of tumor necrosis factor production => GO:0032760 / apolipoprotein binding / positive regulation of amyloid-beta formation / negative regulation of neuron differentiation / transition metal ion binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / regulation of toll-like receptor signaling pathway / associative learning / trans-Golgi network membrane / regulation of NMDA receptor activity / positive regulation of tau-protein kinase activity / positive regulation of excitatory postsynaptic potential / regulation of Wnt signaling pathway / RNA polymerase II core promoter sequence-specific DNA binding / spindle midzone / clathrin-coated pit / chemoattractant activity / regulation of peptidyl-tyrosine phosphorylation / synapse organization
Amyloidogenic glycoprotein, copper-binding domain superfamily / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Beta-amyloid precursor protein C-terminal / Pancreatic trypsin inhibitor Kunitz domain superfamily / Amyloid-beta precursor protein / Amyloidogenic glycoprotein / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Amyloidogenic glycoprotein, E2 domain ...Amyloidogenic glycoprotein, copper-binding domain superfamily / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Beta-amyloid precursor protein C-terminal / Pancreatic trypsin inhibitor Kunitz domain superfamily / Amyloid-beta precursor protein / Amyloidogenic glycoprotein / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Amyloidogenic glycoprotein, E2 domain / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, copper-binding / Proteinase inhibitor I2, Kunitz, conserved site / PH-like domain superfamily / Amyloidogenic glycoprotein, intracellular domain, conserved site / Amyloidogenic glycoprotein, copper-binding domain conserved site / Pancreatic trypsin inhibitor Kunitz domain / Amyloidogenic glycoprotein, amyloid-beta peptide
Amyloid-beta precursor protein
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / SOLID-STATE NMR / helical reconstruction / simulated annealing / cryo EM / Resolution: 2.77 Å|
|Authors||Ghosh, U. / Thurber, K.R. / Tycko, R.|
|Citation||Journal: Proc Natl Acad Sci U S A / Year: 2021|
Title: Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue.
Authors: Ujjayini Ghosh / Kent R Thurber / Wai-Ming Yau / Robert Tycko /
Abstract: Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report ...Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.
SummaryFull reportAbout validation report
|Structure viewer||Molecule: |
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1: Amyloid-beta precursor protein
2: Amyloid-beta precursor protein
3: Amyloid-beta precursor protein
4: Amyloid-beta precursor protein
5: Amyloid-beta precursor protein
6: Amyloid-beta precursor protein
|Symmetry||Helical symmetry: (Circular symmetry: 1 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 6 / Rise per n subunits: 2.45 Å / Rotation per n subunits: 179.66 °)|
Mass: 4335.852 Da / Num. of mol.: 6 / Fragment: UNP residues 653-692 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P05067
|EM experiment||Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction|
|Component||Name: amyloid-beta(1-40) fibrils derived from human AD brain|
Details: Fibrils produced by seeded growth using amyloid-beta in brain extract as the source of seeds. CryoEM and solid state NMR measurements were performed on second-generation seeded fibrils.
Entity ID: #1 / Source: NATURAL
|Molecular weight||Value: 29 kDa/nm / Experimental value: YES|
|Source (natural)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 7.4 |
Details: 10 mM phosphate buffer with 0.01% NaN3 to avoid microbial contamination. Buffers were filtered to avoid contamination.
|Buffer component||Conc.: 10 mM / Name: Phosphate buffer / Formula: Na2HPO4/NaH2PO4|
|Specimen||Conc.: 0.45 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
Details: Protein exists in solution as amyloid fibrils of varying lengths.
|Specimen support||Details: The grids were checked in microscope prior to use. / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3|
|Vitrification||Instrument: LEICA PLUNGER / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 293 K|
Details: The grids were preblotted for 10 seconds and blotted for 6 seconds before plunging.
|Details||Type: fibrous protein|
Contents: 100 uM U-15N,13C amyloid-beta(1-40), phosphate buffer
Details: lyophilized, rehydrated in MAS rotor, 100 uM concentration prior to pelleting
Label: U-labeled fibrils / Solvent system: phosphate buffer
|Sample||Conc.: 100 uM / Component: amyloid-beta(1-40) / Isotopic labeling: U-15N,13C|
|Sample conditions||Details: pelleted, lyophilized, rehydrated in MAS rotor / Ionic strength: 10 mM / Label: conditions_1 / pH: 7.4 / PH err: 0.05 / Pressure: 1 atm / Temperature: 297 K / Temperature err: 2|
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: TFS KRIOS|
Details: Preliminary grid screening was done manually in FEI T12.
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 130000 X / Nominal defocus max: -3000 nm / Nominal defocus min: -500 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE|
|Specimen holder||Cryogen: NITROGEN / Model: FEI TITAN KRIOS AUTOGRID HOLDER / Residual tilt: 6 mradians|
|Image recording||Average exposure time: 10 sec. / Electron dose: 73.5 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1337|
|EM imaging optics||Energyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV|
|Image scans||Movie frames/image: 50 / Used frames/image: 1-50|
|NMR spectrometer||Type: Varian InfinityPlus / Manufacturer: Varian / Model: InfinityPlus / Field strength: 600 MHz|
|Image processing||Details: The selected images were corrected for gain. The gain reference was not rotated or flipped.|
|CTF correction||Details: The correction was done in Gctf and is corrected for amplitude. Per -particle CTF refinement was done prior to final reconstruction.|
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
|Helical symmerty||Angular rotation/subunit: 179.66 ° / Axial rise/subunit: 2.45 Å / Axial symmetry: C1|
|Particle selection||Num. of particles selected: 19790 |
Details: The particles were picked using Relion manual pick, with a 20A low pass filter and particle diameter of 30A.
|3D reconstruction||Resolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14775 / Algorithm: FOURIER SPACE|
Details: A modified version of RELION 3.0-beta was used for the reconstruction. The modified version allowed local averaging of the rotation angle. Final reconstruction used 2-fold screw symmetry.
Num. of class averages: 1 / Symmetry type: HELICAL
|Atomic model building||Protocol: AB INITIO MODEL / Space: REAL|
Details: Xplor-NIH was used to combine EM density with phi/psi restraints from NMR chemical shifts (from Talos-N Version 4.21 Rev 2016.343.11.31).
|Refinement||Method: simulated annealing / Software ordinal: 3 |
Details: phi/psi from TalosN & EM density used as restraints
|NMR representative||Selection criteria: lowest energy|
|NMR ensemble||Conformer selection criteria: structures with the least restraint violations|
Conformers calculated total number: 60 / Conformers submitted total number: 10
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