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- EMDB-40416: Type I beta-amyloid 42 Filaments from Down syndrome -

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Basic information

Entry
Database: EMDB / ID: EMD-40416
TitleType I beta-amyloid 42 Filaments from Down syndrome
Map data
Sample
  • Tissue: Type I beta amyloid 42
    • Protein or peptide: Amyloid-beta protein 42
KeywordsBeta Amyloid filaments / Down Syndrome / NEUROPEPTIDE / Human Trisomy 21
Function / homology
Function and homology information


amyloid-beta complex / growth cone lamellipodium / Aggregated β-amyloid induces FXII autocatalysis / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / hippocampal neuron apoptotic process / microglia development / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands ...amyloid-beta complex / growth cone lamellipodium / Aggregated β-amyloid induces FXII autocatalysis / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / hippocampal neuron apoptotic process / microglia development / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / Aggregated β-amyloid interacts with fibrinogen / 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 / 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 / regulation of long-term neuronal synaptic plasticity / neuronal dense core vesicle / 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 / cellular response to cAMP / neuron projection maintenance / clathrin-coated pit / visual learning / astrocyte activation / synaptic cleft / Mitochondrial protein degradation / platelet alpha granule lumen / regulation of neuron apoptotic process / positive regulation of glycolytic process / response to interleukin-1 / ionotropic glutamate receptor signaling pathway / locomotory behavior / cellular response to copper ion / learning / endosome lumen / positive regulation of interleukin-1 beta production / Regulation of clotting cascade / central nervous system development / positive regulation of long-term synaptic potentiation / serine-type endopeptidase inhibitor activity / endocytosis / protein serine/threonine kinase binding / Post-translational protein phosphorylation / trans-Golgi network membrane / dendritic shaft / microglial cell activation / cellular response to nerve growth factor stimulus / 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 translation / 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 / regulation of gene expression / calcium ion transport
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)
Methodhelical reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsHoq MR / Bharath SR / Vago FS / Jiang W
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)5U01NS110437 and and 1RF1AG071177 United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Cryo-EM structures of amyloid-β and tau filaments in Down syndrome.
Authors: Anllely Fernandez / Md Rejaul Hoq / Grace I Hallinan / Daoyi Li / Sakshibeedu R Bharath / Frank S Vago / Xiaoqi Zhang / Kadir A Ozcan / Kathy L Newell / Holly J Garringer / Wen Jiang / ...Authors: Anllely Fernandez / Md Rejaul Hoq / Grace I Hallinan / Daoyi Li / Sakshibeedu R Bharath / Frank S Vago / Xiaoqi Zhang / Kadir A Ozcan / Kathy L Newell / Holly J Garringer / Wen Jiang / Bernardino Ghetti / Ruben Vidal /
Abstract: Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is ...Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.
History
DepositionApr 10, 2023-
Header (metadata) releaseApr 3, 2024-
Map releaseApr 3, 2024-
UpdateJun 26, 2024-
Current statusJun 26, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40416.png

Downloads & links

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Map

FileDownload / File: emd_40416.map.gz / Format: CCP4 / Size: 589.8 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.05 Å/pix.
x 63 pix.
= 66.402 Å		1.05 Å/pix.
x 57 pix.
= 60.078 Å		1.05 Å/pix.
x 42 pix.
= 44.268 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 1.054 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0134
Minimum - Maximum-0.010028555 - 0.028300561
Average (Standard dev.)0.0018538911 (±0.0046245893)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin10010997
Dimensions574263
Spacing635742
CellA: 66.402 Å / B: 60.078003 Å / C: 44.268 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40416_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40416_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Type I beta amyloid 42

EntireName: Type I beta amyloid 42
Components
  • Tissue: Type I beta amyloid 42
    • Protein or peptide: Amyloid-beta protein 42

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Supramolecule #1: Type I beta amyloid 42

SupramoleculeName: Type I beta amyloid 42 / type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Amyloid-beta protein 42

MacromoleculeName: Amyloid-beta protein 42 / type: protein_or_peptide / ID: 1
Details: Type I beta-amyloid 42 filaments from Down syndrome Case 2
Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.560128 KDa
SequenceString:
GYEVHHQKLV FFAEDVGSNK GAIIGLMVGG VVIA

UniProtKB: Amyloid-beta precursor protein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 1.103 sec. / Average electron dose: 50.46 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 5.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 81000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.38 Å
Applied symmetry - Helical parameters - Δ&Phi: 178.24 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 45575
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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