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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 42Amyloid beta
KeywordsBeta Amyloid filaments / Down Syndrome / NEUROPEPTIDE / Human Trisomy 21
Function / homology
Function and homology information


regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis ...regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / 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 / regulation of Wnt signaling pathway / mating behavior / positive regulation of amyloid fibril formation / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / : / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / presynaptic active zone / nuclear envelope lumen / modulation of excitatory postsynaptic potential / suckling behavior / COPII-coated ER to Golgi transport vesicle / dendrite development / smooth endoplasmic reticulum / regulation of NMDA receptor activity / TRAF6 mediated NF-kB activation / negative regulation of long-term synaptic potentiation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / regulation of presynapse assembly / The NLRP3 inflammasome / intracellular copper ion homeostasis / transition metal ion binding / regulation of multicellular organism growth / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / forebrain development / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / cholesterol metabolic process / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / neuron projection maintenance / positive regulation of glycolytic process / extracellular matrix organization / positive regulation of mitotic cell cycle / response to interleukin-1 / axonogenesis / adult locomotory behavior / trans-Golgi network membrane / dendritic shaft / locomotory behavior / platelet alpha granule lumen / 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 / astrocyte activation / endosome lumen / Post-translational protein phosphorylation / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / positive regulation of JNK cascade / TAK1-dependent IKK and NF-kappa-B activation / neuromuscular junction / visual learning / serine-type endopeptidase inhibitor activity / recycling endosome / cognition / positive regulation of inflammatory response / positive regulation of interleukin-6 production / neuron cellular homeostasis / Golgi lumen / endocytosis / positive regulation of non-canonical NF-kappaB signal transduction / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron projection development / cellular response to amyloid-beta / positive regulation of DNA-binding transcription factor activity / G2/M transition of mitotic cell cycle / cell-cell junction / synaptic vesicle / positive regulation of tumor necrosis factor production / regulation of translation
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)
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-
UpdateApr 10, 2024-
Current statusApr 10, 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)
Voxel sizeX=Y=Z: 1.054 Å
Density
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
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

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 42Amyloid beta

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

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Image processing

Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
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
FSC plot (resolution estimation)

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