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- PDB-9c5r: Structure of recombinantly assembled alpha-synuclein variant fibrils -

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Basic information

Entry
Database: PDB / ID: 9c5r
TitleStructure of recombinantly assembled alpha-synuclein variant fibrils
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / alpha-synuclein fibrils / structural protein
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 / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization ...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 / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / 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 / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of norepinephrine uptake / transporter regulator activity / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / negative regulation of microtubule polymerization / synaptic vesicle transport / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / dynein complex binding / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of exocytosis / response to magnesium ion / synaptic vesicle exocytosis / enzyme inhibitor activity / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / regulation of presynapse assembly / response to type II interferon / alpha-tubulin binding / supramolecular fiber organization / inclusion body / phospholipid metabolic process / cellular response to copper ion / axon terminus / cellular response to epinephrine stimulus / 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 / negative regulation of protein kinase activity / 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 / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / neuron apoptotic process / chemical synaptic transmission / molecular adaptor activity / negative regulation of neuron apoptotic process / response to lipopolysaccharide / histone binding / amyloid fibril formation / lysosome / oxidoreductase activity / transcription cis-regulatory region binding / postsynapse / positive regulation of apoptotic process / Amyloid fiber formation / copper ion binding / response to xenobiotic stimulus / axon / neuronal cell body
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsSun, C.Q. / Zhou, K. / DePaola IV, P. / Lee, V.M.Y. / Li, C. / Zhou, Z.H. / Rodriguez, J.A. / Peng, C. / Jiang, L.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)R01 AG060149 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM071940 United States
CitationJournal: J Biol Chem / Year: 2025
Title: Structural basis of a distinct α-synuclein strain that promotes tau inclusion in neurons.
Authors: Chuanqi Sun / Kang Zhou / Peter DePaola / Cally Li / Virginia M Y Lee / Z Hong Zhou / Chao Peng / Lin Jiang /
Abstract: Amyloidoses are predominantly associated with the accumulation of persistent aggregates of a particular protein. For example, the protein α-synuclein characteristically aggregates in Parkinson's ...Amyloidoses are predominantly associated with the accumulation of persistent aggregates of a particular protein. For example, the protein α-synuclein characteristically aggregates in Parkinson's disease (PD), while amyloid beta and tau deposits are associated with Alzheimer's disease (AD). However, α-synuclein-positive inclusions have been reportedly found in some tauopathies, and vice versa; tau-positive inclusions can be found in synucleinopathies. This suggests that there may be coexistence or crosstalk between these proteinopathies. This coexistence suggests that the simultaneous presence of these misfolded proteins may amplify pathogenic mechanisms. However, the crosstalk between these two types of proteopathies remains poorly understood. We now determine the structure of α-synuclein fibrils that directly promote tau aggregation by cryogenic electron microscopy. Helical reconstruction at 2.6 Å resolution reveals a new α-synuclein fibril polymorph we term "strain B"; its core is unique, incorporating both the N- and C-termini of α-synuclein. The design of peptides meant to inhibit the formation of this structure demonstrates that the C-terminal domain fragment (D105-E115) of α-synuclein is critical for the formation of "strain B" fibrils and may play a key role in its interaction with tau. We hypothesize that the unique structure of pathological α-synuclein significantly contributes to tau co-aggregation and plays a role in the intricate interactions among Alzheimer's, Parkinson's, and other neurodegenerative diseases. These findings open new avenues for drug targeting, discovery, and improve our understanding of neurodegenerative pathology.
History
DepositionJun 6, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 16, 2025Provider: repository / Type: Initial release

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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
D: Alpha-synuclein
E: Alpha-synuclein
F: Alpha-synuclein
G: Alpha-synuclein
H: Alpha-synuclein
I: Alpha-synuclein
J: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)144,76110
Polymers144,76110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
SymmetryHelical symmetry: (Circular symmetry: 1 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 10 / Rise per n subunits: 2.408 Å / Rotation per n subunits: 179.477 °)

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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.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (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: alpha-synuclein / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 60 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris-HCl(HOCH2)3CNHCl1
2150 mMsodium chlorideNaCl1
35 mMdithiothreitol(CH(OH)CH2SH)21
SpecimenConc.: 8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 900 nm / Calibrated defocus min: 700 nm / Calibrated defocus max: 2800 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 recordingAverage exposure time: 3.6 sec. / Electron dose: 48 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4094
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV
Image scansWidth: 5760 / Height: 4092 / Movie frames/image: 5 / Used frames/image: 2-34

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2SerialEMimage acquisition
3DigitalMicrographimage acquisition
5CTFFIND4.1.5CTF correction
8Coot0.8.9model fitting
12RELION3.1.2classification
13RELION3.1.23D reconstruction
14PHENIX1.18.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.477 ° / Axial rise/subunit: 2.408 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 57074
3D reconstructionResolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 26051 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingB value: 53.18 / Protocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 6CU7

6cu7


Pdb chain-ID: A / Accession code: 6CU7 / Source name: PDB / Type: experimental model

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