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- EMDB-63250: Cryo-EM structure of alpha-synuclein P8 fibril -

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Entry
Database: EMDB / ID: EMD-63250
TitleCryo-EM structure of alpha-synuclein P8 fibril
Map data
Sample
  • Organelle or cellular component: Cryo-EM structure of alpha-synuclein P8 fibril
    • Protein or peptide: Alpha-synuclein
KeywordsPROTEIN FIBRIL / amyloid
Function / homology
Function and homology information


PKR-mediated signaling / regulation of neurotransmitter secretion / platelet alpha granule membrane / neurotransmitter secretion / membrane organization / synaptic transmission, dopaminergic / 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 / neurotransmitter secretion / membrane organization / synaptic transmission, dopaminergic / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / 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 / response to iron(II) ion / SNARE complex assembly / regulation of reactive oxygen species metabolic process / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / transporter regulator activity / regulation of locomotion / synaptic vesicle priming / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle transport / positive regulation of receptor recycling / dynein complex binding / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / dopamine metabolic process / cuprous ion binding / positive regulation of endocytosis / protein complex oligomerization / positive regulation of exocytosis / response to magnesium ion / regulation of neuronal synaptic plasticity / kinesin binding / synaptic vesicle endocytosis / regulation of presynapse assembly / response to type II interferon / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / alpha-tubulin binding / positive regulation of synaptic transmission / inclusion body / phospholipid metabolic process / cellular response to copper ion / axon terminus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / excitatory postsynaptic potential / fatty acid metabolic process / phosphoprotein binding / protein tetramerization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / protein destabilization / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / neuron apoptotic process / chemical synaptic transmission / negative regulation of neuron apoptotic process / response to lipopolysaccharide / histone binding / cytoskeleton / oxidoreductase activity / postsynapse / copper ion binding / response to xenobiotic stimulus / neuronal cell body / synapse / calcium ion binding / perinuclear region of cytoplasm / magnesium ion binding / protein-containing complex / mitochondrion / extracellular space
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
Methodhelical reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsXia WC / Tao YQ / Liu C
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Neuron / Year: 2025
Title: Fibril fuzzy coat is important for α-synuclein pathological transmission activity.
Authors: Yuliang Han / Juan Li / Wencheng Xia / Qintong Li / Zihan Sun / Wen Zeng / Yingxin Hu / Kelvin C Luk / Cong Liu / ShengQi Xiang / Zhuohao He /
Abstract: α-synuclein transmission and propagation are hallmarks of synucleinopathies, yet the molecular mechanisms remain elusive. Using α-synuclein preformed fibrils as pathological seeds, we observed a ...α-synuclein transmission and propagation are hallmarks of synucleinopathies, yet the molecular mechanisms remain elusive. Using α-synuclein preformed fibrils as pathological seeds, we observed a gradual decline in neuronal transmission activity during serial propagation. Fibril polymorphisms were identified from the initial generation: mini-P, with higher neuronal seeding activity, and mini-S, which accelerated recombinant α-synuclein aggregation. Changes in their proportions during propagation explained the overall decline in transmission activity. Cryoelectron microscopy and solid-state nuclear magnetic resonance revealed that both fibrils shared similar core regions but differed in their fuzzy coat flexibilities. The interaction between the fuzzy coat and fibril core substantially influenced neuronal transmission, a model further supported by hydrogen/deuterium exchange mass spectrometry. A mini-P-selective antibody identified active fibril types in newly propagated brain regions in human synucleinopathies. This study highlights the fuzzy coat's pivotal role in pathological protein transmission and suggests it as a potential therapeutic target for synucleinopathies.
History
DepositionJan 23, 2025-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_63250.png

Downloads & links

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Map

FileDownload / File: emd_63250.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 360 pix.
= 298.8 Å		0.83 Å/pix.
x 360 pix.
= 298.8 Å		0.83 Å/pix.
x 360 pix.
= 298.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.007
Minimum - Maximum-0.03162275 - 0.06027459
Average (Standard dev.)0.0002010452 (±0.0026559052)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_63250_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_63250_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of alpha-synuclein P8 fibril

EntireName: Cryo-EM structure of alpha-synuclein P8 fibril
Components
  • Organelle or cellular component: Cryo-EM structure of alpha-synuclein P8 fibril
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Cryo-EM structure of alpha-synuclein P8 fibril

SupramoleculeName: Cryo-EM structure of alpha-synuclein P8 fibril / type: organelle_or_cellular_component / 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: 6 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 14.501185 KDa
Recombinant expressionOrganism: Escherichia coli K-12 (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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.4 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.58 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 112926
CTF correctionType: NONE
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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