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- PDB-5aef: Electron cryo-microscopy of an Abeta(1-42)amyloid fibril -

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Basic information

Entry
Database: PDB / ID: 5aef
TitleElectron cryo-microscopy of an Abeta(1-42)amyloid fibril
ComponentsAMYLOID BETA A4 PROTEIN
KeywordsPROTEIN FIBRIL / ALZHEIMER'S DISEASE / AMYLOID FIBRIL / PROTEIN AGGREGATION / PROTEIN FOLDING / CROSS-BETA / FREALIX
Function / homology
Function and homology information


cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of Wnt signaling pathway / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / axon midline choice point recognition ...cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of Wnt signaling pathway / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / suckling behavior / COPII-coated ER to Golgi transport vesicle / dendrite development / presynaptic active zone / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / regulation of presynapse assembly / transition metal ion binding / regulation of multicellular organism growth / negative regulation of neuron differentiation / intracellular copper ion homeostasis / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / protein serine/threonine kinase binding / regulation of peptidyl-tyrosine phosphorylation / clathrin-coated pit / positive regulation of chemokine production / forebrain development / Notch signaling pathway / neuron projection maintenance / positive regulation of G2/M transition of mitotic cell cycle / Mitochondrial protein degradation / positive regulation of protein metabolic process / positive regulation of calcium-mediated signaling / ionotropic glutamate receptor signaling pathway / cholesterol metabolic process / positive regulation of glycolytic process / extracellular matrix organization / positive regulation of mitotic cell cycle / response to interleukin-1 / axonogenesis / adult locomotory behavior / trans-Golgi network membrane / platelet alpha granule lumen / positive regulation of peptidyl-threonine phosphorylation / dendritic shaft / learning / positive regulation of interleukin-1 beta production / positive regulation of long-term synaptic potentiation / central nervous system development / endosome lumen / locomotory behavior / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / synapse organization / regulation of long-term neuronal synaptic plasticity / TAK1-dependent IKK and NF-kappa-B activation / serine-type endopeptidase inhibitor activity / visual learning / neuromuscular junction / recycling endosome / cognition / Golgi lumen / positive regulation of inflammatory response / positive regulation of interleukin-6 production / neuron cellular homeostasis / positive regulation of non-canonical NF-kappaB signal transduction / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle / Platelet degranulation / apical part of cell
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 A4 protein / Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 5 Å
AuthorsSchmidt, M. / Rohou, A. / Lasker, K. / Yadav, J.K. / Schiene-Fischer, C. / Fandrich, M. / Grigorieff, N.
CitationJournal: Proc Natl Acad Sci U S A / Year: 2015
Title: Peptide dimer structure in an Aβ(1-42) fibril visualized with cryo-EM.
Authors: Matthias Schmidt / Alexis Rohou / Keren Lasker / Jay K Yadav / Cordelia Schiene-Fischer / Marcus Fändrich / Nikolaus Grigorieff /
Abstract: Alzheimer's disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) ...Alzheimer's disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy, neuronal dysfunction, and cellular toxicity. Although the connection between AD and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1-42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptide N termini. The observed molecular architecture is compatible with the general chemical properties of Aβ peptide and provides a structural basis for various biological observations that illuminate the molecular underpinnings of AD. Moreover, the structure provides direct evidence for a steric zipper within a fibril formed by full-length Aβ peptide.
History
DepositionAug 29, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 14, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 21, 2015Group: Database references
Revision 1.2Aug 30, 2017Group: Advisory / Category: pdbx_validate_polymer_linkage
Item: _pdbx_validate_polymer_linkage.dist / _pdbx_validate_polymer_linkage.label_alt_id_1 / _pdbx_validate_polymer_linkage.label_alt_id_2
Revision 1.3Oct 3, 2018Group: Data collection / Category: em_software / Item: _em_software.image_processing_id
Revision 1.4Oct 2, 2019Group: Data collection / Other / Category: atom_sites / cell
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.length_a / _cell.length_b / _cell.length_c
Revision 1.5Oct 23, 2019Group: Data collection / Other / Category: cell / Item: _cell.Z_PDB
Revision 1.6May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BA" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 3-STRANDED BARREL THIS IS REPRESENTED BY A 4-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

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Assembly

Deposited unit
A: AMYLOID BETA A4 PROTEIN
B: AMYLOID BETA A4 PROTEIN


Theoretical massNumber of molelcules
Total (without water)5,6712
Polymers5,6712
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA

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Components

#1: Protein/peptide AMYLOID BETA A4 PROTEIN / ABETA17-42


Mass: 2835.365 Da / Num. of mol.: 2 / Fragment: ABETA, UNP RESIDUES 630-657 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: E9PG40, UniProt: P05067*PLUS

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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: ABETA(1-42) AMYLOID-LIKE FIBRIL / Type: COMPLEX / Details: FIBRIL
Buffer solutionName: 50MM TRIS-HCL / pH: 7.4 / Details: 50MM TRIS-HCL
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: HOLEY CARBON
VitrificationInstrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Details: 4 SEC BACKSIDE BLOTTING

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Electron microscopy imaging

Experimental equipment
Model: Tecnai F30 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F30 / Date: Feb 5, 2010
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 59000 X / Calibrated magnification: 58333 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1750 nm / Cs: 2 mm
Specimen holderTemperature: 100 K
Image recordingElectron dose: 30 e/Å2 / Film or detector model: KODAK SO-163 FILM
Image scansNum. digital images: 29

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Processing

EM softwareName: FREALIX / Category: 3D reconstruction
CTF correctionDetails: INDIVIDUAL HELICAL SUBUNITS
3D reconstructionMethod: PROJECTION MATCHING AND FOURIER INVERSION / Resolution: 5 Å / Num. of particles: 62320 / Actual pixel size: 1.2 Å
Details: FINAL MAP WAS CALCULATED FROM 29 SINGLE FILAMENT RECONSTRUCTIONS. DATA USED FOR REFINEMENT WAS NEVER BELOW 10 ANGSTROM RESOLUTION. RESOLUTION OF FIBRIL CORE IS ABOUT 5 ANGSTROM. 3 POSSIBLE ...Details: FINAL MAP WAS CALCULATED FROM 29 SINGLE FILAMENT RECONSTRUCTIONS. DATA USED FOR REFINEMENT WAS NEVER BELOW 10 ANGSTROM RESOLUTION. RESOLUTION OF FIBRIL CORE IS ABOUT 5 ANGSTROM. 3 POSSIBLE MODELS FOR THE CENTRAL REGION OF A ABETA(1-42) FIBRIL RECONSTRUCTION. MODEL1 ABETA(17-42) MODEL2 ABETA( 16-41) MODEL3 ABETA(15-40) SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-3132. (DEPOSITION ID: 13698).
Symmetry type: HELICAL
Atomic model buildingProtocol: OTHER / Space: REAL / Target criteria: ELECTRON DENSITY / Details: METHOD--DIREX REFINEMENT PROTOCOL--PEPTIDE CHAIN
RefinementHighest resolution: 5 Å
Refinement stepCycle: LAST / Highest resolution: 5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms388 0 0 0 388

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