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- EMDB-12268: Type 2AB alpha-synuclein filament seeded in vitro by filaments pu... -

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Basic information

Entry
Database: EMDB / ID: EMD-12268
TitleType 2AB alpha-synuclein filament seeded in vitro by filaments purified from Multiple Systems Atrophy Case 1
Map dataType 2AB alpha-synuclein filament seeded in vitro by filaments purified from Multiple Systems Atrophy Case 1
Sample
  • Complex: Alpha synuclein filament
    • Protein or peptide: Alpha-synuclein
KeywordsAmyloid / Multiple System Atrophy / Neurodegeneration / alpha-synuclein / filament / 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 / 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 / regulation of locomotion / positive regulation of neurotransmitter secretion / negative regulation of dopamine metabolic process / positive regulation of inositol phosphate biosynthetic process / regulation of macrophage activation / regulation of norepinephrine uptake / negative regulation of microtubule polymerization / synaptic vesicle transport / transporter regulator activity / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / mitochondrial ATP synthesis coupled electron transport / regulation of dopamine secretion / 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 endocytosis / positive regulation of exocytosis / synaptic vesicle exocytosis / kinesin binding / synaptic vesicle endocytosis / enzyme inhibitor activity / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / response to type II interferon / regulation of presynapse assembly / 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 / actin binding / growth cone / cellular response to oxidative stress / neuron apoptotic process / cell cortex / response to lipopolysaccharide / histone binding / microtubule binding / molecular adaptor activity / chemical synaptic transmission / amyloid fibril formation / 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)
Methodhelical reconstruction / cryo EM / Resolution: 4.23 Å
AuthorsLovestam SKA / Schweighauser M
Funding support United Kingdom, Japan, 4 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC-U105184291 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Japan Agency for Medical Research and Development (AMED)JP18ek0109391 Japan
Japan Agency for Medical Research and Development (AMED)JP18dm020719 Japan
CitationJournal: FEBS Open Bio / Year: 2021
Title: Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy.
Authors: Sofia Lövestam / Manuel Schweighauser / Tomoyasu Matsubara / Shigeo Murayama / Taisuke Tomita / Takashi Ando / Kazuko Hasegawa / Mari Yoshida / Airi Tarutani / Masato Hasegawa / Michel ...Authors: Sofia Lövestam / Manuel Schweighauser / Tomoyasu Matsubara / Shigeo Murayama / Taisuke Tomita / Takashi Ando / Kazuko Hasegawa / Mari Yoshida / Airi Tarutani / Masato Hasegawa / Michel Goedert / Sjors H W Scheres /
Abstract: The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of α-synuclein into filaments is believed to underlie the prion-like spreading of ...The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of α-synuclein into filaments is believed to underlie the prion-like spreading of protein inclusions in a number of human neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We previously determined the atomic structures of α-synuclein filaments from the putamen of five individuals with MSA. Here, we used filament preparations from three of these brains for the in vitro seeded assembly of recombinant human α-synuclein. We find that the structures of the seeded assemblies differ from those of the seeds, suggesting that additional, as yet unknown, factors play a role in the propagation of the seeds. Identification of these factors will be essential for understanding the prion-like spreading of α-synuclein proteinopathies.
History
DepositionJan 28, 2021-
Header (metadata) releaseFeb 24, 2021-
Map releaseFeb 24, 2021-
UpdateMay 1, 2024-
Current statusMay 1, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.007
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.007
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7ncj
  • Surface level: 0.007
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7ncj
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12268.png

Downloads & links

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Map

FileDownload / File: emd_12268.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationType 2AB alpha-synuclein filament seeded in vitro by filaments purified from Multiple Systems Atrophy Case 1
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.007 / Movie #1: 0.007
Minimum - Maximum-0.045652464 - 0.055649273
Average (Standard dev.)0.00004947454 (±0.0010789107)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z281.600281.600281.600
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ410410410
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0460.0560.000

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Supplemental data

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Half map: Type 2AB alpha-synuclein filament seeded in vitro by...

Fileemd_12268_half_map_1.map
AnnotationType 2AB alpha-synuclein filament seeded in vitro by filaments purified from Multiple Systems Atrophy Case 1, half map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Type 2AB alpha-synuclein filament seeded in vitro by...

Fileemd_12268_half_map_2.map
AnnotationType 2AB alpha-synuclein filament seeded in vitro by filaments purified from Multiple Systems Atrophy Case 1, half map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Alpha synuclein filament

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

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Supramolecule #1: Alpha synuclein filament

SupramoleculeName: Alpha synuclein filament / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
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

Concentration1 mg/mL
BufferpH: 6.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: LMB vitrobot IV.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 32.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm
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 reconstructionApplied symmetry - Helical parameters - Δz: 4.8 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.86 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 4.23 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Software - details: The purple version :) / Number images used: 57358
Startup modelType of model: INSILICO MODEL / Details: Relion helix ini model tool
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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