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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 ...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 / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / 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 / dopamine biosynthetic process / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / negative regulation of dopamine metabolic process / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / regulation of norepinephrine uptake / negative regulation of microtubule polymerization / regulation of locomotion / synaptic vesicle transport / transporter regulator activity / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / regulation of dopamine secretion / mitochondrial ATP synthesis coupled electron transport / dynein complex binding / negative regulation of thrombin-activated receptor signaling pathway / positive regulation of receptor recycling / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / enzyme inhibitor activity / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / response to type II interferon / negative regulation of serotonin uptake / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / phospholipid metabolic process / cellular response to fibroblast growth factor stimulus / inclusion body / axon terminus / Hsp70 protein binding / cellular response to epinephrine stimulus / response to interleukin-1 / regulation of microtubule cytoskeleton organization / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / SNARE binding / 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 / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / terminal bouton / positive regulation of inflammatory response / 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 / chemical synaptic transmission / amyloid fibril formation / molecular adaptor activity / negative regulation of neuron apoptotic process / mitochondrial outer membrane / oxidoreductase activity
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: 2025
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

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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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