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- EMDB-45221: Structure of recombinantly assembled alpha-synuclein variant fibrils -

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Basic information

Entry
Database: EMDB / ID: EMD-45221
TitleStructure of recombinantly assembled alpha-synuclein variant fibrils
Map data
Sample
  • Complex: alpha-synuclein
    • Protein or peptide: Alpha-synuclein
Keywordsalpha-synuclein fibrils / structural protein / PROTEIN FIBRIL
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)
Methodhelical reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsSun CQ / Zhou K / DePaola IV P / Lee VMY / Li C / Zhou ZH / Rodriguez JA / Peng C / Jiang L
Funding support United States, 2 items
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, 2024-
Header (metadata) releaseApr 16, 2025-
Map releaseApr 16, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45221.png

Downloads & links

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Map

FileDownload / File: emd_45221.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 300 pix.
= 323.7 Å		1.08 Å/pix.
x 300 pix.
= 323.7 Å		1.08 Å/pix.
x 300 pix.
= 323.7 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.079 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.06292834 - 0.14507328
Average (Standard dev.)0.00016768387 (±0.0032174282)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 323.7 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_45221_msk_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_45221_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_45221_half_map_2.map
Projections & Slices
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Sample components

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Entire : alpha-synuclein

EntireName: alpha-synuclein
Components
  • Complex: alpha-synuclein
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: alpha-synuclein

SupramoleculeName: alpha-synuclein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60 kDa/nm

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

UniProtKB: Alpha-synuclein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration8 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mM(HOCH2)3CNHClTris-HCl
150.0 mMNaClsodium chloride
5.0 mM(CH(OH)CH2SH)2dithiothreitol
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 40 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.038 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Digitization - Frames/image: 2-34 / Number grids imaged: 1 / Number real images: 4094 / Average exposure time: 3.6 sec. / Average electron dose: 48.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated defocus max: 2.8000000000000003 µm / Calibrated defocus min: 0.7000000000000001 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.9 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 2.408 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.477 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.2) / Number images used: 26051
Segment selectionNumber selected: 57074 / Software - Name: crYOLO
Startup modelType of model: OTHER / Details: A featureless cylinder created by EMAN2
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6cu7


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 53.18
Output model

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

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