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- PDB-8bfz: Amyloid-beta 42 filaments extracted from the human brain with Arc... -

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Basic information

Entry
Database: PDB / ID: 8bfz
TitleAmyloid-beta 42 filaments extracted from the human brain with Arctic mutation (E22G) of Alzheimer's disease | ABeta42
ComponentsAmyloid-beta precursor protein
KeywordsPROTEIN FIBRIL / Amyloid / filaments / amyloid-beta / Arctic mutation / APP / E22G / E693G
Function / homology
Function and homology information


regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / collateral sprouting in absence of injury / cytosolic mRNA polyadenylation / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / Mitochondrial protein degradation / axo-dendritic transport / synaptic assembly at neuromuscular junction ...regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / collateral sprouting in absence of injury / cytosolic mRNA polyadenylation / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / Mitochondrial protein degradation / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of Wnt signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / positive regulation of amyloid fibril formation / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / : / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / protein serine/threonine kinase binding / nuclear envelope lumen / suckling behavior / modulation of excitatory postsynaptic potential / presynaptic active zone / COPII-coated ER to Golgi transport vesicle / dendrite development / smooth endoplasmic reticulum / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / regulation of presynapse assembly / intracellular copper ion homeostasis / transition metal ion binding / regulation of multicellular organism growth / negative regulation of long-term synaptic potentiation / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / forebrain development / regulation of peptidyl-tyrosine phosphorylation / clathrin-coated pit / positive regulation of chemokine production / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / ionotropic glutamate receptor signaling pathway / positive regulation of protein metabolic process / neuron projection maintenance / cholesterol metabolic process / extracellular matrix organization / positive regulation of glycolytic process / positive regulation of mitotic cell cycle / response to interleukin-1 / axonogenesis / adult locomotory behavior / trans-Golgi network membrane / dendritic shaft / platelet alpha granule lumen / locomotory behavior / positive regulation of peptidyl-threonine phosphorylation / learning / central nervous system development / positive regulation of interleukin-1 beta production / positive regulation of long-term synaptic potentiation / endosome lumen / astrocyte activation / Post-translational protein phosphorylation / synapse organization / positive regulation of JNK cascade / regulation of long-term neuronal synaptic plasticity / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation / visual learning / neuromuscular junction / serine-type endopeptidase inhibitor activity / recycling endosome / cognition / Golgi lumen / positive regulation of inflammatory response / endocytosis / neuron cellular homeostasis / positive regulation of interleukin-6 production / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to amyloid-beta / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron projection development / G2/M transition of mitotic cell cycle / cell-cell junction / synaptic vesicle / positive regulation of tumor necrosis factor production
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. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / 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 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: 2.8 Å
AuthorsYang, Y. / Zhang, W.J. / Murzin, A.G. / Schweighauser, M. / Huang, M. / Lovestam, S.K.A. / Peak-Chew, S.Y. / Macdonald, J. / Lavenir, I. / Ghetti, B. ...Yang, Y. / Zhang, W.J. / Murzin, A.G. / Schweighauser, M. / Huang, M. / Lovestam, S.K.A. / Peak-Chew, S.Y. / Macdonald, J. / Lavenir, I. / Ghetti, B. / Graff, C. / Kumar, A. / Nordberg, A. / Goedert, M. / Scheres, S.H.W.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025-1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
CitationJournal: Acta Neuropathol / Year: 2023
Title: Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains.
Authors: Yang Yang / Wenjuan Zhang / Alexey G Murzin / Manuel Schweighauser / Melissa Huang / Sofia Lövestam / Sew Y Peak-Chew / Takashi Saito / Takaomi C Saido / Jennifer Macdonald / Isabelle ...Authors: Yang Yang / Wenjuan Zhang / Alexey G Murzin / Manuel Schweighauser / Melissa Huang / Sofia Lövestam / Sew Y Peak-Chew / Takashi Saito / Takaomi C Saido / Jennifer Macdonald / Isabelle Lavenir / Bernardino Ghetti / Caroline Graff / Amit Kumar / Agneta Nordberg / Michel Goedert / Sjors H W Scheres /
Abstract: The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo- ...The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo-EM structures of Aβ filaments from the frontal cortex of a previously described case (AβPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II Aβ42. When compared to the structures of wild-type Aβ42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aβ molecules and promote filament formation. A minority of Aβ42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aβ filaments with the Arctic mutation from mouse knock-in line App. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (App murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The App murine Arctic fold differs from the human Arctic folds, but shares some substructure.
History
DepositionOct 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 18, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author / refine
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _refine.ls_d_res_high / _refine.ls_d_res_low

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)9,0402
Polymers9,0402
Non-polymers00
Water0
1
A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein

A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein

A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)27,1216
Polymers27,1216
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_5551
point symmetry operation2
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2generate(0.998728, 0.050428), (-0.050428, 0.998728), (1)-4.81482, 5.06407, 4.79398
3generate(0.998728, -0.050428), (0.050428, 0.998728), (1)5.06407, -4.81482, -4.79398

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Components

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


Mass: 4520.087 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / 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-beta 42 dimeric filaments extracted from the human brain with Arctic mutation (E22G) of Alzheimer's disease
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 FIELDBright-field microscopy / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0352 / Classification: refinement
EM software
IDNameCategoryDetails
1RELIONparticle selection
2EPUimage acquisition
4RELIONCTF correction
7Cootmodel fitting
9RELIONinitial Euler assignment
10RELIONfinal Euler assignment
11RELIONclassification
12RELION3D reconstruction
13REFMACmodel refinementservalcat
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -2.92 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C2
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 34191 / Symmetry type: HELICAL
RefinementResolution: 2.8→2.8 Å / Cor.coef. Fo:Fc: 0.863 / SU B: 9.169 / SU ML: 0.171 / ESU R: 0.172
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.38205 --
obs0.38205 18779 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 65.302 Å2
Refinement stepCycle: 1 / Total: 442
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0060.012448
ELECTRON MICROSCOPYr_bond_other_d00.016454
ELECTRON MICROSCOPYr_angle_refined_deg1.2571.598602
ELECTRON MICROSCOPYr_angle_other_deg0.5091.5811040
ELECTRON MICROSCOPYr_dihedral_angle_1_deg7.197560
ELECTRON MICROSCOPYr_dihedral_angle_2_deg
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.2711072
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0720.272
ELECTRON MICROSCOPYr_gen_planes_refined0.0060.02504
ELECTRON MICROSCOPYr_gen_planes_other0.0020.0288
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it7.4555.962246
ELECTRON MICROSCOPYr_mcbond_other7.4495.954246
ELECTRON MICROSCOPYr_mcangle_it11.6848.908304
ELECTRON MICROSCOPYr_mcangle_other11.7118.925305
ELECTRON MICROSCOPYr_scbond_it8.7817.432202
ELECTRON MICROSCOPYr_scbond_other8.7637.434203
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other15.05710.717299
ELECTRON MICROSCOPYr_long_range_B_refined20.24671.652423
ELECTRON MICROSCOPYr_long_range_B_other20.2671.823424
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.79→2.863 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.516 1376 -
obs--100 %

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