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- PDB-8eze: Brain-derived 42-residue amyloid-beta fibril type B -

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Basic information

Entry
Database: PDB / ID: 8eze
TitleBrain-derived 42-residue amyloid-beta fibril type B
ComponentsBeta-amyloid protein 42
KeywordsPROTEIN FIBRIL / amyloid-b 42 (Ab42) fibril / Alzheimer' / s disease (AD) / Polymorphism.
Function / homology
Function and homology information


amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / hippocampal neuron apoptotic process ...amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / hippocampal neuron apoptotic process / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of synapse structure or activity / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / Golgi-associated vesicle / PTB domain binding / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / astrocyte projection / Lysosome Vesicle Biogenesis / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / positive regulation of protein metabolic process / TRAF6 mediated NF-kB activation / negative regulation of long-term synaptic potentiation / signaling receptor activator activity / Advanced glycosylation endproduct receptor signaling / transition metal ion binding / main axon / The NLRP3 inflammasome / modulation of excitatory postsynaptic potential / regulation of multicellular organism growth / intracellular copper ion homeostasis / ECM proteoglycans / regulation of presynapse assembly / positive regulation of T cell migration / neuronal dense core vesicle / response to insulin-like growth factor stimulus / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / Notch signaling pathway / cellular response to manganese ion / swimming behavior / clathrin-coated pit / extracellular matrix organization / neuron projection maintenance / astrocyte activation / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / ionotropic glutamate receptor signaling pathway / Mitochondrial protein degradation / response to interleukin-1 / axonogenesis / protein serine/threonine kinase binding / platelet alpha granule lumen / regulation of neuron apoptotic process / cellular response to copper ion / cellular response to cAMP / positive regulation of glycolytic process / central nervous system development / dendritic shaft / trans-Golgi network membrane / endosome lumen / positive regulation of long-term synaptic potentiation / positive regulation of interleukin-1 beta production / adult locomotory behavior / learning / Post-translational protein phosphorylation / locomotory behavior / serine-type endopeptidase inhibitor activity / microglial cell activation / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to nerve growth factor stimulus / TAK1-dependent IKK and NF-kappa-B activation / recycling endosome / synapse organization / regulation of long-term neuronal synaptic plasticity / visual learning / positive regulation of JNK cascade / response to lead ion / Golgi lumen / positive regulation of interleukin-6 production / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / endocytosis / neuron projection development / positive regulation of tumor necrosis factor production / positive regulation of inflammatory response / calcium ion transport / Platelet degranulation / heparin binding / regulation of translation / regulation of gene expression
Similarity search - Function
Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site ...Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsTycko, R. / Lee, M. / Yau, Y.-M. / Louis, J.M.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Structures of brain-derived 42-residue amyloid-β fibril polymorphs with unusual molecular conformations and intermolecular interactions.
Authors: Myungwoon Lee / Wai-Ming Yau / John M Louis / Robert Tycko /
Abstract: Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible ...Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible molecular structures. Previous studies of Aβ42 fibrils, including fibrils prepared entirely in vitro or extracted from brain tissue and using solid-state NMR (ssNMR) or cryogenic electron microscopy (cryo-EM) methods, have found polymorphs with differences in amino acid sidechain orientations, lengths of structurally ordered segments, and contacts between cross-β subunit pairs within a single filament. Despite these differences, Aβ42 molecules adopt a common S-shaped conformation in all previously described high-resolution Aβ42 fibril structures. Here we report two cryo-EM-based structures of Aβ42 fibrils that are qualitatively different, in samples derived from AD brain tissue by seeded growth. In type A fibrils, residues 12 to 42 adopt a ν-shaped conformation, with both intra-subunit and intersubunit hydrophobic contacts to form a compact core. In type B fibrils, residues 2 to 42 adopt an υ-shaped conformation, with only intersubunit contacts and internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied K28-A42 salt bridges in type A fibrils. The coexistence of two predominant polymorphs, with differences in N-terminal dynamics, is supported by ssNMR data, as is faithful propagation of structures from first-generation to second-generation brain-seeded Aβ42 fibril samples. These results demonstrate that Aβ42 fibrils can exhibit a greater range of structural variations than seen in previous studies.
History
DepositionOct 31, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-amyloid protein 42
B: Beta-amyloid protein 42
C: Beta-amyloid protein 42
D: Beta-amyloid protein 42
E: Beta-amyloid protein 42
F: Beta-amyloid protein 42
G: Beta-amyloid protein 42
H: Beta-amyloid protein 42


Theoretical massNumber of molelcules
Total (without water)36,1618
Polymers36,1618
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Number of models9

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Components

#1: Protein/peptide
Beta-amyloid protein 42 / Amyloid beta A4 protein / ABPP / APPI / APP / Alzheimer disease amyloid protein / Amyloid precursor ...Amyloid beta A4 protein / ABPP / APPI / APP / Alzheimer disease amyloid protein / Amyloid precursor protein / Beta-amyloid precursor protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 4520.087 Da / Num. of mol.: 8 / Fragment: residues 672-713
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P05067

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: amyloid-b 42 (Ab42) fibril / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 4514.10 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4 / Details: 10mM Na-phosphate, 0.1% sodium azide
Buffer componentConc.: 10 mM / Name: Sodium Phosphate
SpecimenConc.: 0.34 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: The grid was glow discharged immediately before use.
Grid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK I / Cryogen name: ETHANE / Humidity: 99 % / Chamber temperature: 93 K
Details: Preblot for 12-13 seconds and blot for 2.5-3.0 seconds before plunging

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 1.65 sec. / Electron dose: 50.34 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5557
Image scansWidth: 11520 / Height: 8184 / Movie frames/image: 22

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Processing

EM software
IDNameVersionCategory
1RELION4.0.0particle selection
4RELION4.0.0CTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10UCSF Chimeramodel refinement
11X-PLORXplor-NIHmodel refinement
12RELION4.0.0initial Euler assignment
13RELION4.0.0final Euler assignment
14RELION4.0.0classification
15RELION4.0.03D reconstruction
Image processingDetails: Gatan Imaging Filter (GIF) Quantum LS
CTF correctionDetails: CTFFIND-4 / Type: NONE
Helical symmertyAngular rotation/subunit: 179.36 ° / Axial rise/subunit: 2.48 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 285760
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 92019 / Algorithm: FOURIER SPACE
Details: 3D refinement and post-processing were performed with 21 (screw) symmetry
Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingProtocol: OTHER
Details: Manually generated model was fit into the density using PHENIX and UCSF Chimera. Further refinements were performed using Xplor-NIH.

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