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- PDB-9ic7: Cryo-EM structure of alpha-synuclein fibrils formed in artificial... -

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Basic information

Entry
Database: PDB / ID: 9ic7
TitleCryo-EM structure of alpha-synuclein fibrils formed in artificial cerebrospinal fluid (aCSF)
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / Parkinson / CSF / alpha-synuclein / neurodegeneration
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 / regulation of synaptic vesicle recycling ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / mitochondrial membrane organization / negative regulation of exocytosis / 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 / Lewy body / 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 / protein kinase inhibitor activity / synaptic vesicle transport / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / positive regulation of receptor recycling / positive regulation of exocytosis / cuprous ion binding / nuclear outer membrane / mitochondrial ATP synthesis coupled electron transport / dynein complex binding / synaptic vesicle exocytosis / response to magnesium ion / positive regulation of endocytosis / negative regulation of serotonin uptake / response to type II interferon / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / kinesin binding / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / phospholipid metabolic process / supramolecular fiber organization / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / cellular response to epinephrine stimulus / inclusion body / Hsp70 protein binding / enzyme inhibitor activity / response to interleukin-1 / axon terminus / cellular response to copper ion / 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 / protein sequestering activity / excitatory postsynaptic potential / tubulin binding / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / phospholipid binding / synapse organization / receptor internalization / regulation of long-term neuronal synaptic plasticity / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / growth cone / actin binding / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / amyloid fibril formation / chemical synaptic transmission
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsSnieckute, R. / Sulskis, D. / Jocyte, A. / Venclovaite, U. / Tamulyte, R. / Ziaunys, M. / Smirnovas, V. / Sakalauskas, A.
Funding supportLithuania, European Union, 3items
OrganizationGrant numberCountry
Research Council of LithuaniaS-PD-22-91Lithuania
European Regional Development Fund01.1.1-CPVA-V-701-07-0001European Union
Other government24381
CitationJournal: Adv Sci (Weinh) / Year: 2026
Title: Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid.
Authors: Rūta Sniečkutė / Darius Šulskis / Arūnė Jocytė / Urtė Venclovaitė / Rimgailė Tamulytė / Mantas Žiaunys / Vytautas Smirnovas / Andrius Sakalauskas
Abstract: α-Synuclein (aSyn) is an intrinsically disordered protein involved in neurotransmission and synaptic plasticity. The pathological aggregation of this protein is a hallmark of synucleinopathies such ...α-Synuclein (aSyn) is an intrinsically disordered protein involved in neurotransmission and synaptic plasticity. The pathological aggregation of this protein is a hallmark of synucleinopathies such as Parkinson's disease (PD) or Multiple System Atrophy (MSA). Misfolded aSyn, which primarily originates in the cell cytosol, transmits between neurons, promoting a prion-like propagation. However, extracellular environments such as interstitial and cerebrospinal fluids (ISF & CSF) play a major role in its clearance and pathological transformation. The molecular components of CSF, including proteins, glycosaminoglycans, and metal ions, may influence the aggregate morphology, structure, and cytotoxicity to cells. To better understand how extracellular composition affects aggregates and their formation, artificial cerebrospinal fluid (aCSF) is employed to mimic potential aggregation processes occurring in CSF. Distinct aSyn fibrils are observed that exhibited low stability outside aCSF, and the removal of key CSF components led to its structural alterations. Cryo-electron microscopy revealed that these fibrils possess an electron density pocket coordinated with polar basic AAs (K43, K45, H50) that is also observed in aggregates obtained from PD and MSA patients. The findings illustrate the importance of physiologically relevant conditions in studying aSyn aggregation and may explain why disease-related fibril structure replication in vitro has not yet been successful.
History
DepositionFeb 14, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 18, 2026Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.year / _em_admin.last_update
Revision 1.1Feb 18, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin / Data content type: EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
n: Alpha-synuclein
a: Alpha-synuclein
b: Alpha-synuclein
c: Alpha-synuclein
d: Alpha-synuclein
e: Alpha-synuclein
f: Alpha-synuclein
g: Alpha-synuclein
h: Alpha-synuclein
i: Alpha-synuclein
j: Alpha-synuclein
k: Alpha-synuclein
l: Alpha-synuclein
m: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)202,66614
Polymers202,66614
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: 14476.108 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P37840
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: Amyloid fibrils of alpha-synuclein formed in artificial cerebrospinal fluid
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.2044 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.33
Details: Once all components were mixed together, the pH was adjusted by supplementing 1.6 microliters of 25% HCl to yield pH of 7.33.
Buffer component
IDConc.NameFormulaBuffer-ID
1127 mMSodium chlorideNaCl1
21.8 mMPotassium chlorideKCl1
31.2 mMPotassium phosphateKH2PO41
47.81 mMDisodium phosphateNa2HPO41
53.19 mMSodium phosphateNaH2PO41
64 mMD-GlucoseC6H12O61
71.4 mMCalcium chlorideCaCl21
81.3 mMMagnesium chlorideMgCl21
96.5 mMUreaCH4N2O1
100.00615 mMHuman Serum AlbumineHSA1
110.0052 mMCholesterolC27H46O1
122.4 mMSocium lactateC3H5NaO31
130.7 mMGlutamineC5H10N2O31
SpecimenConc.: 0.723 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was homogenous.
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 92000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 30 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION5particle selection
2EPUimage acquisition
4CTFFINDCTF correction
7Cootmodel fitting
9RELIONinitial Euler assignment
10RELIONfinal Euler assignment
11RELIONclassification
12RELION53D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmerty
IDImage processing-IDAngular rotation/subunit (°)Axial rise/subunit (Å)Axial symmetry
11-1.14.91C2
21-1.14.91C2
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 20772 / Algorithm: FOURIER SPACE / Symmetry type: HELICAL

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