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- EMDB-42294: Structure of recombinantly assembled murine alpha-synuclein fibrils -

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Basic information

Entry
Database: EMDB / ID: EMD-42294
TitleStructure of recombinantly assembled murine alpha-synuclein fibrils
Map data
Sample
  • Complex: alpha-synuclein
    • Protein or peptide: Alpha-synuclein
Keywordssynuclein / Parkinson's disease / neurodegeneration / amyloid / fibril / PROTEIN FIBRIL
Function / homology
Function and homology information


PKR-mediated signaling / regulation of neurotransmitter secretion / platelet alpha granule membrane / membrane organization / synaptic transmission, dopaminergic / neurotransmitter secretion / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake ...PKR-mediated signaling / regulation of neurotransmitter secretion / platelet alpha granule membrane / membrane organization / synaptic transmission, dopaminergic / neurotransmitter secretion / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / arachidonate binding / regulation of reactive oxygen species metabolic process / dopamine biosynthetic process / SNARE complex assembly / response to iron(II) ion / positive regulation of neurotransmitter secretion / positive regulation of inositol phosphate biosynthetic process / regulation of locomotion / negative regulation of dopamine metabolic process / regulation of macrophage activation / transporter regulator activity / negative regulation of microtubule polymerization / synaptic vesicle transport / synaptic vesicle priming / mitochondrial ATP synthesis coupled electron transport / regulation of dopamine secretion / dynein complex binding / positive regulation of receptor recycling / negative regulation of thrombin-activated receptor signaling pathway / dopamine metabolic process / cuprous ion binding / protein complex oligomerization / nuclear outer membrane / response to magnesium ion / positive regulation of endocytosis / positive regulation of exocytosis / kinesin binding / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / regulation of neuronal synaptic plasticity / response to type II interferon / regulation of presynapse assembly / alpha-tubulin binding / positive regulation of synaptic transmission / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / cellular response to copper ion / phospholipid metabolic process / cellular response to fibroblast growth factor stimulus / inclusion body / axon terminus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / adult locomotory behavior / excitatory postsynaptic potential / phosphoprotein binding / protein tetramerization / microglial cell activation / fatty acid metabolic process / regulation of long-term neuronal synaptic plasticity / ferrous iron binding / synapse organization / protein destabilization / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / terminal bouton / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / cellular response to oxidative stress / growth cone / cell cortex / histone binding / neuron apoptotic process / response to lipopolysaccharide / microtubule binding / chemical synaptic transmission / mitochondrial outer membrane / negative regulation of neuron apoptotic process / cytoskeleton / oxidoreductase activity / postsynapse
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
Methodhelical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsZhou Y / Sokratian A
Funding support United States, 1 items
OrganizationGrant numberCountry
Michael J. Fox FoundationASAP-020527 United States
CitationJournal: Sci Adv / Year: 2024
Title: Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases.
Authors: Arpine Sokratian / Ye Zhou / Meltem Tatli / Kevin J Burbidge / Enquan Xu / Elizabeth Viverette / Sonia Donzelli / Addison M Duda / Yuan Yuan / Huizhong Li / Samuel Strader / Nirali Patel / ...Authors: Arpine Sokratian / Ye Zhou / Meltem Tatli / Kevin J Burbidge / Enquan Xu / Elizabeth Viverette / Sonia Donzelli / Addison M Duda / Yuan Yuan / Huizhong Li / Samuel Strader / Nirali Patel / Lauren Shiell / Tuyana Malankhanova / Olivia Chen / Joseph R Mazzulli / Lalith Perera / Henning Stahlberg / Mario Borgnia / Alberto Bartesaghi / Hilal A Lashuel / Andrew B West /
Abstract: The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson's disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in ...The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson's disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here, we report the first atomic structure of mouse α-synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse α-synuclein fibrils display altered packing arrangements, reduced hydrophobicity, and heightened fragmentation sensitivity and evoke only weak immunological responses. Furthermore, mouse α-synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized α-synuclein mice. These findings provide critical insights into the structural underpinnings of α-synuclein pathogenicity and emphasize a need to reassess the role of mouse α-synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.
History
DepositionOct 10, 2023-
Header (metadata) releaseOct 9, 2024-
Map releaseOct 9, 2024-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42294.png

Downloads & links

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Map

FileDownload / File: emd_42294.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
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AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 128 pix.
= 138.24 Å		1.08 Å/pix.
x 128 pix.
= 138.24 Å		1.08 Å/pix.
x 128 pix.
= 138.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0146
Minimum - Maximum-0.053710554 - 0.08037511
Average (Standard dev.)0.00011187801 (±0.0037834584)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 138.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_42294_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_42294_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : alpha-synuclein

EntireName: alpha-synuclein
Components
  • Complex: alpha-synuclein
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: alpha-synuclein

SupramoleculeName: alpha-synuclein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 14.501185 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVTTVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGNIA AATGFVKKDQ MGKGEEGYPQ EGILEDMPVD PGSEAYEMPS EEGYQDYEPE A

UniProtKB: Alpha-synuclein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
137.0 mMNaClSodium Chloride
2.7 mMKClPotassium Chloride
10.0 mMNa2HPO4Sodium Phosphate Dibasic
1.8 mMKH2PO4Potassium Phosphate Monobasic

Details: Phosphate-buffered saline (PBS)
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 50 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 75 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293.15 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 2 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
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: 4.84 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.84 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 27523
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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