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- PDB-8azt: Type II amyloid-beta 42 filaments from high-spin supernatants of ... -

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Basic information

Entry
Database: PDB / ID: 8azt
TitleType II 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


amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / hippocampal neuron apoptotic process / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of Wnt signaling pathway / axo-dendritic transport ...amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / hippocampal neuron apoptotic process / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of Wnt signaling pathway / axo-dendritic transport / axon midline choice point recognition / regulation of synapse structure or activity / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / Golgi-associated vesicle / PTB domain binding / astrocyte projection / Lysosome Vesicle Biogenesis / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / neuron remodeling / nuclear envelope lumen / dendrite development / regulation of multicellular organism growth / TRAF6 mediated NF-kB activation / positive regulation of protein metabolic process / signaling receptor activator activity / negative regulation of long-term synaptic potentiation / transition metal ion binding / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / modulation of excitatory postsynaptic potential / main axon / intracellular copper ion homeostasis / ECM proteoglycans / response to insulin-like growth factor stimulus / positive regulation of T cell migration / regulation of presynapse assembly / Notch signaling pathway / neuronal dense core vesicle / swimming behavior / Purinergic signaling in leishmaniasis infection / positive regulation of mitotic cell cycle / adult locomotory behavior / cellular response to manganese ion / positive regulation of chemokine production / extracellular matrix organization / positive regulation of calcium-mediated signaling / axonogenesis / neuron projection maintenance / clathrin-coated pit / Mitochondrial protein degradation / ionotropic glutamate receptor signaling pathway / astrocyte activation / platelet alpha granule lumen / response to interleukin-1 / regulation of neuron apoptotic process / positive regulation of glycolytic process / cellular response to cAMP / cellular response to copper ion / endosome lumen / trans-Golgi network membrane / positive regulation of interleukin-1 beta production / learning / protein serine/threonine kinase binding / dendritic shaft / positive regulation of long-term synaptic potentiation / central nervous system development / Post-translational protein phosphorylation / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / locomotory behavior / microglial cell activation / cellular response to nerve growth factor stimulus / visual learning / positive regulation of non-canonical NF-kappaB signal transduction / TAK1-dependent IKK and NF-kappa-B activation / synapse organization / positive regulation of JNK cascade / recycling endosome / response to lead ion / positive regulation of interleukin-6 production / Golgi lumen / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / neuron projection development / endocytosis / calcium ion transport / positive regulation of inflammatory response / positive regulation of tumor necrosis factor production / 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, heparin-binding / Amyloid A4 N-terminal heparin-binding / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide ...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, heparin-binding / Amyloid A4 N-terminal heparin-binding / 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, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / 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: 3.7 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
Citation
Journal: 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.
#1: Journal: Biorxiv / Year: 2022
Title: Abundant A beta fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains
Authors: Stern, A.M. / Yang, Y. / Meunier, A.L. / Liu, W. / Cai, Y. / Ericsson, M. / Liu, L. / Goedert, M. / Scheres, S.H.W. / Selkoe, D.J.
History
DepositionSep 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 2.0Nov 23, 2022Group: Atomic model / Data collection ...Atomic model / Data collection / Refinement description / Structure summary
Category: atom_site / em_software ...atom_site / em_software / pdbx_contact_author / pdbx_validate_torsion / refine / refine_hist / refine_ls_restr / refine_ls_shell / software
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.occupancy / _refine.B_iso_mean / _refine.correlation_coeff_Fo_to_Fc / _refine.details / _refine.ls_R_factor_R_work / _refine.ls_R_factor_all / _refine.ls_R_factor_obs / _refine.ls_d_res_low / _refine.ls_number_reflns_R_work / _refine.ls_number_reflns_obs / _refine.ls_percent_reflns_R_free / _refine.ls_wR_factor_R_work / _refine.overall_SU_B / _refine.overall_SU_ML / _refine.pdbx_average_fsc_free / _refine.pdbx_average_fsc_overall / _refine.pdbx_average_fsc_work / _refine.pdbx_overall_ESU_R / _refine.pdbx_stereochemistry_target_values / _refine.solvent_model_details / _software.contact_author / _software.contact_author_email / _software.date / _software.description / _software.version
Description: Model orientation/position
Details: Rotated the carboxylate group of residue Ala42 faces outward, and the sidechain of Ala42 points to other hydrophobic residues Ala30.
Provider: author / Type: Coordinate replacement
Revision 2.1May 24, 2023Group: Database references / Refinement description
Category: citation / citation_author / pdbx_initial_refinement_model
Revision 2.2Jul 19, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 2.3Jul 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)4,5201
Polymers4,5201
Non-polymers00
Water00
1
B: 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(0.998785, -0.049286), (0.049286, 0.998785), (1)5.37167, -5.11314, -4.806
3generate(-1), (-1), (1)212.73599, 212.73599
4generate(0.998785, 0.049286), (-0.049286, 0.998785), (1)-5.11314, 5.37167, 4.806

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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 II 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 FIELD / 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: 5.8.0352 / Classification: refinement
EM software
IDNameCategoryDetails (eV)
7Cootmodel fitting
12RELION3D reconstruction
13REFMACmodel refinementServalcat
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -2.8 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C2
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14740 / Symmetry type: HELICAL
Atomic model buildingPDB-ID: 7Q4M

7q4m


Accession code: 7Q4M / Source name: PDB / Type: experimental model
RefinementResolution: 3.7→74.79 Å / Cor.coef. Fo:Fc: 0.928 / SU B: 18.776 / SU ML: 0.264 / ESU R: 0.213
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.36452 --
obs0.36452 9995 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 112.804 Å2
Refinement stepCycle: 1 / Total: 226
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0090.012229
ELECTRON MICROSCOPYr_bond_other_d0.0010.016230
ELECTRON MICROSCOPYr_angle_refined_deg1.8431.603308
ELECTRON MICROSCOPYr_angle_other_deg0.7671.579528
ELECTRON MICROSCOPYr_dihedral_angle_1_deg10.268530
ELECTRON MICROSCOPYr_dihedral_angle_2_deg
ELECTRON MICROSCOPYr_dihedral_angle_3_deg16.5741038
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0830.237
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.02256
ELECTRON MICROSCOPYr_gen_planes_other0.0030.0244
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_it13.75410.245123
ELECTRON MICROSCOPYr_mcbond_other13.72410.224123
ELECTRON MICROSCOPYr_mcangle_it20.24115.402152
ELECTRON MICROSCOPYr_mcangle_other20.23615.412153
ELECTRON MICROSCOPYr_scbond_it14.67512.659106
ELECTRON MICROSCOPYr_scbond_other14.60712.641107
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other25.02118.087157
ELECTRON MICROSCOPYr_long_range_B_refined32.9910242
ELECTRON MICROSCOPYr_long_range_B_other32.9440243
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.7→3.796 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.546 744 -
obs--100 %

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