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- EMDB-10652: Multiple system atrophy Type II-2 alpha-synuclein filament -

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Basic information

Entry
Database: EMDB / ID: EMD-10652
TitleMultiple system atrophy Type II-2 alpha-synuclein filament
Map dataHelical symmetry imposed relion post-processed map.
Sample
  • Tissue: Sarkosyl-insoluble fractions from the putamen of multiple system atrophy brain
    • Protein or peptide: Alpha-synuclein
Keywordsmultiple system atrophy / 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 / 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 / negative regulation of chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process / transporter regulator activity / 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 / regulation of locomotion / synaptic vesicle priming / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / 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 endocytosis / positive regulation of exocytosis / response to magnesium ion / synaptic vesicle exocytosis / enzyme inhibitor activity / kinesin binding / synaptic vesicle endocytosis / regulation of presynapse assembly / response to type II interferon / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / 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 / long-term synaptic potentiation / synapse organization / ferrous iron binding / protein destabilization / PKR-mediated signaling / tau protein binding / phospholipid binding / receptor internalization / synaptic vesicle membrane / positive regulation of inflammatory response / 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 / postsynapse / transcription cis-regulatory region binding / positive regulation of apoptotic process / copper ion binding / Amyloid fiber formation / 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: 3.09 Å
AuthorsSchweighauser M / Shi Y
Funding support United Kingdom, Japan, United States, 7 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
Innovative Medicines Initiative116060 United Kingdom
Japan Agency for Medical Research and Development (AMED)JP18ek0109391 Japan
Japan Agency for Medical Research and Development (AMED)JP18dm020719 Japan
National Institutes of Health/National Institute on Aging (NIH/NIA)P30AG010133 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)U01NS110437 United States
CitationJournal: Nature / Year: 2020
Title: Structures of α-synuclein filaments from multiple system atrophy.
Authors: Manuel Schweighauser / Yang Shi / Airi Tarutani / Fuyuki Kametani / Alexey G Murzin / Bernardino Ghetti / Tomoyasu Matsubara / Taisuke Tomita / Takashi Ando / Kazuko Hasegawa / Shigeo ...Authors: Manuel Schweighauser / Yang Shi / Airi Tarutani / Fuyuki Kametani / Alexey G Murzin / Bernardino Ghetti / Tomoyasu Matsubara / Taisuke Tomita / Takashi Ando / Kazuko Hasegawa / Shigeo Murayama / Mari Yoshida / Masato Hasegawa / Sjors H W Scheres / Michel Goedert /
Abstract: Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases. ...Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases. Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies, the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous α-synuclein inclusions in the human brain.
History
DepositionJan 30, 2020-
Header (metadata) releaseFeb 12, 2020-
Map releaseFeb 12, 2020-
UpdateMay 22, 2024-
Current statusMay 22, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6xyq
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6xyq
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_10652.png

Downloads & links

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Map

FileDownload / File: emd_10652.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHelical symmetry imposed relion post-processed map.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 220 pix.
= 253. Å		1.15 Å/pix.
x 220 pix.
= 253. Å		1.15 Å/pix.
x 220 pix.
= 253. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025 / Movie #1: 0.025
Minimum - Maximum-0.065219104 - 0.13315769
Average (Standard dev.)0.00087757973 (±0.007240183)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 253.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.151.151.15
M x/y/z220220220
origin x/y/z0.0000.0000.000
length x/y/z253.000253.000253.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS220220220
D min/max/mean-0.0650.1330.001

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Supplemental data

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Mask #1

Fileemd_10652_msk_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

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Additional map: Relion post-processed map.

Fileemd_10652_additional.map
AnnotationRelion post-processed map.
Projections & Slices
AxesZYX

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Density Histograms

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Half map: #1

Fileemd_10652_half_map_1.map
Projections & Slices
AxesZYX

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Histogram

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Half map: #2

Fileemd_10652_half_map_2.map
Projections & Slices
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Sample components

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Entire : Sarkosyl-insoluble fractions from the putamen of multiple system ...

EntireName: Sarkosyl-insoluble fractions from the putamen of multiple system atrophy brain
Components
  • Tissue: Sarkosyl-insoluble fractions from the putamen of multiple system atrophy brain
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Sarkosyl-insoluble fractions from the putamen of multiple system ...

SupramoleculeName: Sarkosyl-insoluble fractions from the putamen of multiple system atrophy brain
type: tissue / 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: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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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: 47.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.72 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.34 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF
Details: Helical reconstruction in RELION3. The initial model was reconstructed from reference-free 2-D class averages and the resolution of the cryo-EM map was good enough to do de-novo modelling.
Number images used: 93137
Startup modelType of model: INSILICO MODEL
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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