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- PDB-9wtw: Amyloid-beta 40 Flemish (A21G) mutant Filaments from Human Brain -

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Basic information

Entry
Database: PDB / ID: 9wtw
TitleAmyloid-beta 40 Flemish (A21G) mutant Filaments from Human Brain
ComponentsAmyloid-beta protein 40
KeywordsPROTEIN FIBRIL / Amyloid-beta / Alzheimer's disease / Neurodegeneration / Protein aggregation
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 / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / 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 / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / axon midline choice point recognition / regulation of synapse structure or activity / positive regulation of synaptic transmission, cholinergic / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / peptidase activator activity / PTB domain binding / Golgi-associated vesicle / Lysosome Vesicle Biogenesis / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / neuron remodeling / astrocyte projection / regulation of multicellular organism growth / nuclear envelope lumen / dendrite development / TRAF6 mediated NF-kB activation / positive regulation of protein metabolic process / negative regulation of long-term synaptic potentiation / signaling receptor activator activity / Notch signaling pathway / transition metal ion binding / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / intracellular copper ion homeostasis / modulation of excitatory postsynaptic potential / main axon / ECM proteoglycans / positive regulation of T cell migration / response to insulin-like growth factor stimulus / regulation of presynapse assembly / extracellular matrix organization / swimming behavior / adult locomotory behavior / neuronal dense core vesicle / regulation of long-term neuronal synaptic plasticity / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / positive regulation of chemokine production / positive regulation of mitotic cell cycle / axonogenesis / cellular response to manganese ion / neuron projection maintenance / clathrin-coated pit / visual learning / cellular response to cAMP / astrocyte activation / synaptic cleft / Mitochondrial protein degradation / response to interleukin-1 / platelet alpha granule lumen / regulation of neuron apoptotic process / positive regulation of glycolytic process / learning / ionotropic glutamate receptor signaling pathway / locomotory behavior / cellular response to copper ion / endosome lumen / positive regulation of interleukin-1 beta production / central nervous system development / positive regulation of long-term synaptic potentiation / protein serine/threonine kinase binding / serine-type endopeptidase inhibitor activity / Post-translational protein phosphorylation / dendritic shaft / trans-Golgi network membrane / endocytosis / microglial cell activation / cellular response to nerve growth factor stimulus / regulation of translation / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of interleukin-6 production / positive regulation of JNK cascade / synapse organization / TAK1-dependent IKK and NF-kappa-B activation / Golgi lumen / recycling endosome / response to lead ion / 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 / calcium ion transport / positive regulation of inflammatory response / regulation of gene expression / 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, 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: 1.98 Å
AuthorsGuillen-Poza, P.A. / Yang, Y. / Hervas, R.
Funding support Hong Kong, 1items
OrganizationGrant numberCountry
Other government Hong Kong
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Distinct amyloid-β filament fold in individuals with APP Flemish mutation.
Authors: Peerzada Shariq Shaheen Khaki / Pablo Adrian Guillen-Poza / Carlton Wong / Chloe Kan / Rakesh Sharma / Rio Sugimura / Andrew C Robinson / Alejandro Valbuena / Roy Chun-Laam Ng / Yang Yang / Ruben Hervas /
Abstract: The dominantly inherited Flemish mutation-an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)-causes a rare, early-onset form of Alzheimer ...The dominantly inherited Flemish mutation-an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)-causes a rare, early-onset form of Alzheimer disease characterized by pronounced cerebral amyloid angiopathy and unusually large senile plaque cores. Here, we report cryo-electron microscopy structures of amyloid filaments extracted from the postmortem parietal lobes of two individuals representing the only two known Flemish pedigrees worldwide. Although tau paired helical filaments were present, the predominant filaments comprise Aβ40-A21G, assembled as two identical protofilaments (D1-V40) packed with two-start helical symmetry. Aβ40-A21G and wild-type Aβ42 filaments share a substructure preceding the substitution site (Y10-F19); however, loss of the methyl group at residue 21 gives rise to a distinct arrangement, termed the 'Flemish fold', which differs from all previously characterized Aβ folds and is defined by a unique hydrophobic interface. Using a cell-based assay, we find that this distinctive fold is associated with the vascular tropism characteristic of the Flemish variant. Together, our structural and cellular data define a familial Alzheimer-disease-associated amyloid fold and provide insight into the molecular basis of Flemish-type dementia and cerebral hemorrhage.
History
DepositionSep 17, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 5, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Amyloid-beta protein 40
J: Amyloid-beta protein 40
I: Amyloid-beta protein 40
H: Amyloid-beta protein 40
G: Amyloid-beta protein 40
A: Amyloid-beta protein 40
D: Amyloid-beta protein 40
C: Amyloid-beta protein 40
F: Amyloid-beta protein 40
E: Amyloid-beta protein 40


Theoretical massNumber of molelcules
Total (without water)43,21810
Polymers43,21810
Non-polymers00
Water72140
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 4321.826 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P05067
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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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 40 (A21G) Flemish filaments extracted from human brain with Alzheimer's disease
Type: TISSUE / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION5particle selection
13RELION53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.817 ° / Axial rise/subunit: 4.882 Å / Axial symmetry: C2
3D reconstructionResolution: 1.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 38206 / Symmetry type: HELICAL
RefinementResolution: 1.98→1.98 Å / Cor.coef. Fo:Fc: 0.821 / SU B: 4.481 / SU ML: 0.104 / ESU R: 0.066
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.3557 --
obs0.3557 85783 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 54.546 Å2
Refinement stepCycle: 1 / Total: 602
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.012606
ELECTRON MICROSCOPYr_bond_other_d00.016560
ELECTRON MICROSCOPYr_angle_refined_deg1.4671.795812
ELECTRON MICROSCOPYr_angle_other_deg0.5761.7471284
ELECTRON MICROSCOPYr_dihedral_angle_1_deg7.074576
ELECTRON MICROSCOPYr_dihedral_angle_2_deg1.6352
ELECTRON MICROSCOPYr_dihedral_angle_3_deg11.2331096
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.080.284
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.02720
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02144
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_it4.4714.496310
ELECTRON MICROSCOPYr_mcbond_other4.4554.491310
ELECTRON MICROSCOPYr_mcangle_it7.0218.043384
ELECTRON MICROSCOPYr_mcangle_other7.0458.056385
ELECTRON MICROSCOPYr_scbond_it9.9016.419296
ELECTRON MICROSCOPYr_scbond_other9.8856.427297
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other16.29111.012429
ELECTRON MICROSCOPYr_long_range_B_refined20.12646.58510
ELECTRON MICROSCOPYr_long_range_B_other20.04846.63509
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.714 6367 -
obs--100 %

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