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- PDB-8bg9: Murine amyloid-beta filaments with the Arctic mutation (E22G) fro... -

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Basic information

Entry
Database: PDB / ID: 8bg9
TitleMurine amyloid-beta filaments with the Arctic mutation (E22G) from APP(NL-G-F) mouse brains | ABeta
ComponentsAmyloid-beta protein 40
KeywordsPROTEIN FIBRIL / Amyloid / amyloid-beta / Arctic mutation / APP / NL-G-F / mouse brains / filaments / E22G / E693G
Function / homology
Function and homology information


regulation of response to calcium ion / Formyl peptide receptors bind formyl peptides and many other ligands / growth cone lamellipodium / cellular response to norepinephrine stimulus / Advanced glycosylation endproduct receptor signaling / growth cone filopodium / ECM proteoglycans / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / TRAF6 mediated NF-kB activation / Lysosome Vesicle Biogenesis ...regulation of response to calcium ion / Formyl peptide receptors bind formyl peptides and many other ligands / growth cone lamellipodium / cellular response to norepinephrine stimulus / Advanced glycosylation endproduct receptor signaling / growth cone filopodium / ECM proteoglycans / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / TRAF6 mediated NF-kB activation / Lysosome Vesicle Biogenesis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Post-translational protein phosphorylation / G alpha (q) signalling events / TAK1-dependent IKK and NF-kappa-B activation / G alpha (i) signalling events / response to yeast / peptidase activator activity / Platelet degranulation / growth factor receptor binding / antifungal humoral response / astrocyte projection / Mitochondrial protein degradation / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / 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 / ciliary rootlet / PTB domain binding / Golgi-associated vesicle / main axon / positive regulation of amyloid fibril formation / neuron remodeling / COPII-coated ER to Golgi transport vesicle / suckling behavior / nuclear envelope lumen / dendrite development / neuronal dense core vesicle / presynaptic active zone / modulation of excitatory postsynaptic potential / neuromuscular process controlling balance / 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 / positive regulation of T cell migration / spindle midzone / smooth endoplasmic reticulum / 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 / positive regulation of protein metabolic process / cholesterol metabolic process / positive regulation of calcium-mediated signaling / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / response to interleukin-1 / extracellular matrix organization / positive regulation of mitotic cell cycle / axonogenesis / adult locomotory behavior / positive regulation of interleukin-1 beta production / dendritic shaft / positive regulation of peptidyl-threonine phosphorylation / positive regulation of long-term synaptic potentiation / central nervous system development / long-term synaptic potentiation / locomotory behavior / positive regulation of JNK cascade / microglial cell activation / regulation of long-term neuronal synaptic plasticity / serine-type endopeptidase inhibitor activity / neuromuscular junction / visual learning / neuron differentiation / recycling endosome / memory / cognition / positive regulation of inflammatory response / positive regulation of interleukin-6 production / neuron cellular homeostasis / positive regulation of non-canonical NF-kappaB signal transduction / endocytosis / cellular response to amyloid-beta / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / neuron projection development
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. / 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 ...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. / 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 speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.5 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. / Nordber, 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 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Amyloid-beta protein 40
B: Amyloid-beta protein 40


Theoretical massNumber of molelcules
Total (without water)8,1612
Polymers8,1612
Non-polymers00
Water00
1
A: Amyloid-beta protein 40
B: Amyloid-beta protein 40

A: Amyloid-beta protein 40
B: Amyloid-beta protein 40

A: Amyloid-beta protein 40
B: Amyloid-beta protein 40


Theoretical massNumber of molelcules
Total (without water)24,4836
Polymers24,4836
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation2
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2generate(0.99974, -0.022792), (0.022792, 0.99974), (1)2.77544, -2.71288, 4.92018
3generate(0.99974, 0.022792), (-0.022792, 0.99974), (1)-2.71288, 2.77544, -4.92018

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Components

#1: Protein/peptide Amyloid-beta protein 40 / Abeta40 / Beta-APP40


Mass: 4080.538 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P12023

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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 filaments extracted from the mouse brains with APP NL-G-F mutations
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Mus musculus (house mouse)
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: 2600 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
IDNameCategory
1RELIONparticle selection
2EPUimage acquisition
4RELIONCTF correction
7Cootmodel fitting
9REFMACmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.347 ° / Axial rise/subunit: 2.46009 Å / Axial symmetry: C1
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 39823 / Symmetry type: HELICAL
RefinementResolution: 3.5→91.5 Å / Cor.coef. Fo:Fc: 0.874 / SU B: 32.782 / SU ML: 0.489 / ESU R: 0.409
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.45765 --
obs0.45765 10897 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 89.99 Å2
Refinement stepCycle: 1 / Total: 564
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0050.012576
ELECTRON MICROSCOPYr_bond_other_d00.016512
ELECTRON MICROSCOPYr_angle_refined_deg1.2431.634770
ELECTRON MICROSCOPYr_angle_other_deg0.5251.61184
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.366572
ELECTRON MICROSCOPYr_dihedral_angle_2_deg3.5152
ELECTRON MICROSCOPYr_dihedral_angle_3_deg16.8941090
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0620.278
ELECTRON MICROSCOPYr_gen_planes_refined0.0050.02672
ELECTRON MICROSCOPYr_gen_planes_other0.0030.02128
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_it7.9418.644294
ELECTRON MICROSCOPYr_mcbond_other7.9488.622293
ELECTRON MICROSCOPYr_mcangle_it12.73412.919364
ELECTRON MICROSCOPYr_mcangle_other12.72812.938365
ELECTRON MICROSCOPYr_scbond_it7.2689.78282
ELECTRON MICROSCOPYr_scbond_other7.2569.793283
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other12.61314.248407
ELECTRON MICROSCOPYr_long_range_B_refined19.35619.356627
ELECTRON MICROSCOPYr_long_range_B_other19.34219.342628
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.5→3.591 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.26 818 -
obs--100 %

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