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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


neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / mitochondrial membrane organization / regulation of glutamate secretion / PKR-mediated signaling / regulation of macrophage activation / positive regulation of neurotransmitter secretion / regulation of neurotransmitter secretion / regulation of locomotion / platelet alpha granule membrane ...neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / mitochondrial membrane organization / regulation of glutamate secretion / PKR-mediated signaling / regulation of macrophage activation / positive regulation of neurotransmitter secretion / regulation of neurotransmitter secretion / regulation of locomotion / platelet alpha granule membrane / membrane organization / mitochondrial ATP synthesis coupled electron transport / regulation of reactive oxygen species metabolic process / arachidonate binding / 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 / negative regulation of chaperone-mediated autophagy / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / dopamine biosynthetic process / negative regulation of dopamine metabolic process / response to iron(II) ion / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of thrombin-activated receptor signaling pathway / dopamine metabolic process / Lewy body / negative regulation of microtubule polymerization / synaptic vesicle priming / synaptic vesicle transport / regulation of norepinephrine uptake / transporter regulator activity / phospholipid metabolic process / positive regulation of inositol phosphate biosynthetic process / protein complex oligomerization / regulation of dopamine secretion / positive regulation of receptor recycling / regulation of neuronal synaptic plasticity / cuprous ion binding / positive regulation of exocytosis / nuclear outer membrane / dynein complex binding / synaptic transmission, dopaminergic / synaptic vesicle exocytosis / response to magnesium ion / positive regulation of endocytosis / negative regulation of serotonin uptake / kinesin binding / positive regulation of synaptic transmission / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / adult locomotory behavior / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / response to type II interferon / inclusion body / fatty acid metabolic process / response to interleukin-1 / Hsp70 protein binding / cytoplasmic vesicle membrane / excitatory postsynaptic potential / positive regulation of release of sequestered calcium ion into cytosol / cellular response to copper ion / axon terminus / enzyme inhibitor activity / glutathione metabolic process / regulation of microtubule cytoskeleton organization / SNARE binding / regulation of long-term neuronal synaptic plasticity / protein tetramerization / protein sequestering activity / receptor internalization / phosphoprotein binding / microglial cell activation / tubulin binding / protein destabilization / ferrous iron binding / synapse organization / phospholipid binding / tau protein binding / neuron apoptotic process / long-term synaptic potentiation / enzyme activator activity / positive regulation of inflammatory response / terminal bouton / actin cytoskeleton / synaptic vesicle / synaptic vesicle membrane / presynapse / growth cone / response to lipopolysaccharide / cellular response to oxidative stress
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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