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Basic information
Entry | Database: EMDB / ID: EMD-10651 | ||||||||||||||||||||||||
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Title | Multiple system atrophy Type II-1 alpha-synuclein filament | ||||||||||||||||||||||||
![]() | Helical symmetries imposed relion post-processed map. | ||||||||||||||||||||||||
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![]() | multiple system atrophy / alpha-synuclein filament / PROTEIN FIBRIL | ||||||||||||||||||||||||
Function / homology | ![]() negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of phospholipase activity / negative regulation of monooxygenase activity / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of phospholipase activity / negative regulation of monooxygenase activity / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / negative regulation of transporter activity / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / regulation of synaptic vesicle recycling / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / regulation of norepinephrine uptake / response to iron(II) ion / dopamine biosynthetic process / SNARE complex assembly / positive regulation of neurotransmitter secretion / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of macrophage activation / dopamine uptake involved in synaptic transmission / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / positive regulation of exocytosis / synaptic vesicle exocytosis / kinesin binding / positive regulation of endocytosis / mitochondrial ATP synthesis coupled electron transport / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / alpha-tubulin binding / localization / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / Hsp70 protein binding / cellular response to epinephrine stimulus / excitatory postsynaptic potential / response to interleukin-1 / adult locomotory behavior / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / fatty acid metabolic process / long-term synaptic potentiation / regulation of transmembrane transporter activity / phosphoprotein binding / protein tetramerization / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / protein destabilization / ferrous iron binding / PKR-mediated signaling / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / tau protein binding / positive regulation of protein serine/threonine kinase activity / receptor internalization / phospholipid binding / synaptic vesicle membrane / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / actin binding / cell cortex / cellular response to oxidative stress / histone binding / growth cone / postsynapse / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / molecular adaptor activity / oxidoreductase activity / lysosome / transcription cis-regulatory region binding Similarity search - Function | ||||||||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.29 Å | ||||||||||||||||||||||||
![]() | Schweighauser M / Shi Y | ||||||||||||||||||||||||
Funding support | ![]() ![]() ![]()
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![]() | ![]() 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 |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 13.4 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.4 KB 17.4 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 7.9 KB | Display | ![]() |
Images | ![]() | 195.1 KB | ||
Masks | ![]() | 40.6 MB | ![]() | |
Filedesc metadata | ![]() | 5.2 KB | ||
Others | ![]() ![]() ![]() | 37.2 MB 31.1 MB 31.2 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 481.6 KB | Display | ![]() |
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Full document | ![]() | 480.7 KB | Display | |
Data in XML | ![]() | 13.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6xypMC ![]() 6xyoC ![]() 6xyqC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | |
EM raw data | ![]() Data size: 1.1 TB Data #1: Unaligned multi-frame movies [micrographs - multiframe] Data #2: Dose-weighted aligned micrographs [micrographs - single frame] Data #3: Polished particle stacks [picked particles - single frame - processed]) |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Helical symmetries imposed relion post-processed map. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.15 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
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Density Histograms |
-Additional map: Relion post-processed map.
File | emd_10651_additional.map | ||||||||||||
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Annotation | Relion post-processed map. | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_10651_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_10651_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : Sarkosyl-insoluble fractions from the putamen of multiple system ...
Entire | Name: Sarkosyl-insoluble fractions from the putamen of multiple system atrophy brain |
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Components |
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-Supramolecule #1: Sarkosyl-insoluble fractions from the putamen of multiple system ...
Supramolecule | Name: Sarkosyl-insoluble fractions from the putamen of multiple system atrophy brain type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Alpha-synuclein
Macromolecule | Name: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 14.476108 KDa |
Sequence | String: MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A UniProtKB: Alpha-synuclein |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | helical reconstruction |
Aggregation state | filament |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 47.5 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |