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- PDB-8azs: Type I amyloid-beta 42 filaments from high-spin supernatants of a... -

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Basic information

Entry
Database: PDB / ID: 8azs
TitleType I amyloid-beta 42 filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | ABeta42
ComponentsAmyloid-beta precursor protein
KeywordsPROTEIN FIBRIL / amyloid / filaments / Abeta42 / amyloid-beta / cryo-EM
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 / regulation of Wnt signaling pathway / 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 / regulation of Wnt signaling pathway / 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 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 / protein serine/threonine kinase binding / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / : / nuclear envelope lumen / suckling behavior / presynaptic active zone / dendrite development / COPII-coated ER to Golgi transport vesicle / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / regulation of presynapse assembly / transition metal ion binding / Mitochondrial protein degradation / intracellular copper ion homeostasis / regulation of multicellular organism growth / negative regulation of long-term synaptic potentiation / negative regulation of neuron differentiation / ECM proteoglycans / smooth endoplasmic reticulum / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / forebrain development / clathrin-coated pit / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / neuron projection maintenance / cholesterol metabolic process / response to interleukin-1 / positive regulation of glycolytic process / positive regulation of mitotic cell cycle / extracellular matrix organization / axonogenesis / adult locomotory behavior / trans-Golgi network membrane / dendritic shaft / platelet alpha granule lumen / locomotory behavior / positive regulation of peptidyl-threonine phosphorylation / learning / positive regulation of interleukin-1 beta production / central nervous system development / positive regulation of long-term synaptic potentiation / endosome lumen / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation / visual learning / serine-type endopeptidase inhibitor activity / neuromuscular junction / recycling endosome / cognition / positive regulation of inflammatory response / Golgi lumen / neuron cellular homeostasis / endocytosis / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to amyloid-beta / positive regulation of interleukin-6 production / 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 / positive regulation of tumor necrosis factor production / cell-cell junction / synaptic vesicle
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: 2.9 Å
AuthorsYang, Y. / Stern, M.A. / Meunier, L.A. / Liu, W. / Cai, Y.Q. / Ericsson, M. / Liu, L. / Selkoe, J.D. / Goedert, M. / Scheres, H.W.S.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
CitationJournal: Neuron / Year: 2023
Title: Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains.
Authors: Andrew M Stern / Yang Yang / Shanxue Jin / Keitaro Yamashita / Angela L Meunier / Wen Liu / Yuqi Cai / Maria Ericsson / Lei Liu / Michel Goedert / Sjors H W Scheres / Dennis J Selkoe /
Abstract: Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed ...Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design.
History
DepositionSep 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Database references / Refinement description
Category: citation / citation_author / pdbx_initial_refinement_model
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 19, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)4,5201
Polymers4,5201
Non-polymers00
Water0
1
H: Amyloid-beta precursor protein
x 6


Theoretical massNumber of molelcules
Total (without water)27,1216
Polymers27,1216
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation5
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2generate(0.998529, -0.054218), (0.054218, 0.998529), (1)5.92354, -5.61063, -4.79488
3generate(-0.999632, 0.027119), (-0.027119, -0.999632), (1)209.81227, 215.58147, -2.39744
4generate(-0.999632, -0.027119), (0.027119, -0.999632), (1)215.58147, 209.81227, 2.39744
5generate(0.998529, 0.054218), (-0.054218, 0.998529), (1)-5.61063, 5.92354, 4.79488
6generate(-0.996692, -0.081277), (0.081277, -0.996692), (1)221.0294, 203.73875, 7.19232

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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.: 1 / 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: Type I amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain
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: 2400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0350 / Classification: refinement / Contact author: Garib N. Murshudov / Contact author email: garib[at]mrc-lmb.cam.ac.uk / Date: May 11, 2022
Description: (un)restrained refinement or idealisation of macromolecular structures
EM software
IDNameCategoryDetails
7Cootmodel fitting
12RELION3D reconstruction
13REFMACmodel refinementServalcat
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 178.4 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 37380 / Symmetry type: HELICAL
Atomic model buildingPDB-ID: 7Q4B

7q4b

RefinementResolution: 2.9→81.438 Å / Cor.coef. Fo:Fc: 0.879 / WRfactor Rwork: 0.327 / SU B: 6.973 / SU ML: 0.13 / Average fsc free: 0 / Average fsc overall: 0.8793 / Average fsc work: 0.8793 / ESU R: 0.103
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rwork0.3274 22441 -
all0.3274 --
obs--100 %
Solvent computationSolvent model: NONE
Displacement parametersBiso mean: 68.479 Å2
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0080.012255
ELECTRON MICROSCOPYr_bond_other_d00.016247
ELECTRON MICROSCOPYr_angle_refined_deg1.3631.59343
ELECTRON MICROSCOPYr_angle_other_deg0.5161.56568
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.203533
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.2041041
ELECTRON MICROSCOPYr_dihedral_angle_6_deg16.3921010
ELECTRON MICROSCOPYr_chiral_restr0.0730.239
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.02289
ELECTRON MICROSCOPYr_gen_planes_other0.0010.0251
ELECTRON MICROSCOPYr_nbd_refined0.1880.232
ELECTRON MICROSCOPYr_symmetry_nbd_other0.1830.2182
ELECTRON MICROSCOPYr_nbtor_refined0.170.2129
ELECTRON MICROSCOPYr_symmetry_nbtor_other0.0770.2157
ELECTRON MICROSCOPYr_xyhbond_nbd_refined0.0670.21
ELECTRON MICROSCOPYr_symmetry_nbd_refined0.1130.26
ELECTRON MICROSCOPYr_nbd_other0.2030.239
ELECTRON MICROSCOPYr_mcbond_it8.1586.232135
ELECTRON MICROSCOPYr_mcbond_other8.0996.196135
ELECTRON MICROSCOPYr_mcangle_it12.1549.336167
ELECTRON MICROSCOPYr_mcangle_other12.5219.398168
ELECTRON MICROSCOPYr_scbond_it9.6817.496120
ELECTRON MICROSCOPYr_scbond_other9.6427.524121
ELECTRON MICROSCOPYr_scangle_it16.30410.755176
ELECTRON MICROSCOPYr_scangle_other16.25810.787177
ELECTRON MICROSCOPYr_lrange_it21.68276.156250
ELECTRON MICROSCOPYr_lrange_other22.03676.716251
LS refinement shell

Refine-ID: ELECTRON MICROSCOPY / Num. reflection Rfree: 0 / Total num. of bins used: 20 / % reflection obs: 100 %

Resolution (Å)Rfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc workWRfactor Rwork
2.9-2.9751.31816771.31816770.6631.318
2.975-3.0570.73815790.73815790.7470.738
3.057-3.1450.62815700.62815700.8190.628
3.145-3.2420.50915570.50915570.8470.509
3.242-3.3480.4314880.4314880.8780.43
3.348-3.4650.3714430.3714430.8790.37
3.465-3.5960.30913440.30913440.9210.309
3.596-3.7420.27413720.27413720.9270.274
3.742-3.9080.26212720.26212720.9290.262
3.908-4.0990.27111870.27111870.9280.271
4.099-4.320.26411460.26411460.9420.264
4.32-4.5810.27411010.27411010.950.274
4.581-4.8960.25610440.25610440.9640.256
4.896-5.2870.2379470.2379470.9690.237
5.287-5.7890.2028950.2028950.9720.202
5.789-6.4680.2448040.2448040.9490.244
6.468-7.4610.3196960.3196960.8790.319
7.461-9.1190.3416040.3416040.8780.341
9.119-12.8160.3554470.3554470.8940.355
12.816-81.4380.4742670.4742670.9170.474

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