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- PDB-9k23: Cryo-EM structure of alpha-synuclein Mini S fibril -

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Basic information

Entry
Database: PDB / ID: 9k23
TitleCryo-EM structure of alpha-synuclein Mini S fibril
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / amyloid
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 / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / arachidonate binding / regulation of reactive oxygen species metabolic process / positive regulation of protein localization to cell periphery / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / SNARE complex assembly / negative regulation of dopamine metabolic process / positive regulation of neurotransmitter secretion / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / regulation of locomotion / synaptic vesicle transport / negative regulation of microtubule polymerization / transporter regulator activity / synaptic vesicle priming / dopamine metabolic process / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / dynein complex binding / mitochondrial ATP synthesis coupled electron transport / positive regulation of receptor recycling / protein complex oligomerization / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of exocytosis / positive regulation of endocytosis / regulation of neuronal synaptic plasticity / kinesin binding / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / positive regulation of synaptic transmission / response to type II interferon / negative regulation of serotonin uptake / regulation of presynapse assembly / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / phospholipid metabolic process / axon terminus / inclusion body / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / adult locomotory behavior / excitatory postsynaptic potential / protein tetramerization / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / regulation of long-term neuronal synaptic plasticity / 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 / growth cone / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / chemical synaptic transmission / negative regulation of neuron apoptotic process / oxidoreductase activity / mitochondrial outer membrane / cytoskeleton / postsynapse
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsXia, W.C. / Liu, C.
Funding support1items
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
DepositionOct 17, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 23, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Alpha-synuclein
A: Alpha-synuclein
C: Alpha-synuclein
E: Alpha-synuclein
D: Alpha-synuclein
F: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)87,0076
Polymers87,0076
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Alpha-synuclein / Non-A beta component of AD amyloid / Non-A4 component of amyloid precursor / NACP


Mass: 14501.185 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Snca, Syn / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: O55042
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of alpha-synuclein Mini S fibril / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 179.55 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 347516 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0052784
ELECTRON MICROSCOPYf_angle_d0.4633762
ELECTRON MICROSCOPYf_dihedral_angle_d10.3631632
ELECTRON MICROSCOPYf_chiral_restr0.05492
ELECTRON MICROSCOPYf_plane_restr0.002468

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