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- PDB-9lon: Cryo-EM structure of alpha-synuclein P8 fibril -

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Basic information

Entry
Database: PDB / ID: 9lon
TitleCryo-EM structure of alpha-synuclein P8 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 / 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 ...PKR-mediated signaling / regulation of neurotransmitter secretion / platelet alpha granule membrane / 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 / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / arachidonate binding / negative regulation of chaperone-mediated autophagy / positive regulation of protein localization to cell periphery / mitochondrial membrane organization / negative regulation of exocytosis / regulation of reactive oxygen species metabolic process / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / positive regulation of neurotransmitter secretion / regulation of macrophage activation / negative regulation of dopamine metabolic process / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of thrombin-activated receptor signaling pathway / regulation of locomotion / negative regulation of microtubule polymerization / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of norepinephrine uptake / transporter regulator activity / synaptic vesicle transport / dopamine metabolic process / regulation of dopamine secretion / protein complex oligomerization / positive regulation of receptor recycling / positive regulation of exocytosis / cuprous ion binding / mitochondrial ATP synthesis coupled electron transport / nuclear outer membrane / dynein complex binding / response to magnesium ion / synaptic vesicle exocytosis / positive regulation of endocytosis / regulation of neuronal synaptic plasticity / negative regulation of serotonin uptake / response to type II interferon / kinesin binding / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / positive regulation of synaptic transmission / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / phospholipid metabolic process / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / inclusion body / Hsp70 protein binding / enzyme inhibitor activity / response to interleukin-1 / axon terminus / cellular response to copper ion / cytoplasmic vesicle membrane / positive regulation of release of sequestered calcium ion into cytosol / regulation of microtubule cytoskeleton organization / SNARE binding / adult locomotory behavior / glutathione metabolic process / protein tetramerization / excitatory postsynaptic potential / protein sequestering activity / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / regulation of long-term neuronal synaptic plasticity / synapse organization / receptor internalization / phospholipid binding / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / synaptic vesicle / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / growth cone / presynapse / actin binding / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3 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
DepositionJan 23, 2025Deposition 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
A: Alpha-synuclein
B: 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 P8 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: 179.58 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 112926 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0092784
ELECTRON MICROSCOPYf_angle_d0.5643762
ELECTRON MICROSCOPYf_dihedral_angle_d7.3581632
ELECTRON MICROSCOPYf_chiral_restr0.051492
ELECTRON MICROSCOPYf_plane_restr0.002468

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