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Yorodumi- EMDB-15285: Cryo-EM structure of alpha-synuclein filaments from Parkinson's d... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-15285 | |||||||||||||||
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Title | Cryo-EM structure of alpha-synuclein filaments from Parkinson's disease and dementia with Lewy bodies | |||||||||||||||
Map data | ||||||||||||||||
Sample |
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Function / homology | Function and homology information 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 / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / 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 / response to iron(II) ion / regulation of norepinephrine uptake / dopamine biosynthetic process / SNARE complex assembly / positive regulation of neurotransmitter secretion / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / regulation of macrophage activation / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / positive regulation of endocytosis / 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 / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / kinesin binding / alpha-tubulin binding / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / 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 / ferrous iron binding / synapse organization / phospholipid binding / protein tetramerization / phosphoprotein binding / microglial cell activation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / tau protein binding / protein destabilization / PKR-mediated signaling / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of protein serine/threonine kinase activity / receptor internalization / synaptic vesicle membrane / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / cellular response to oxidative stress / positive regulation of peptidyl-serine phosphorylation / actin binding / cell cortex / growth cone / histone binding / chemical synaptic transmission / postsynapse / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / lysosome / molecular adaptor activity / oxidoreductase activity / transcription cis-regulatory region binding Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) / human (human) | |||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.2 Å | |||||||||||||||
Authors | Yang Y / Shi Y / Schweighauser M / Zhang XJ / Kotecha A / Murzin AG / Garringer HJ / Cullinane P / Saito Y / Foroud T ...Yang Y / Shi Y / Schweighauser M / Zhang XJ / Kotecha A / Murzin AG / Garringer HJ / Cullinane P / Saito Y / Foroud T / Warner TT / Hasegawa K / Vidal R / Murayama S / Revesz T / Ghetti B / Hasegawa M / Lashley T / Scheres HWS / Goedert M | |||||||||||||||
Funding support | United Kingdom, United States, 4 items
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Citation | Journal: Nature / Year: 2022 Title: Structures of α-synuclein filaments from human brains with Lewy pathology. Authors: Yang Yang / Yang Shi / Manuel Schweighauser / Xianjun Zhang / Abhay Kotecha / Alexey G Murzin / Holly J Garringer / Patrick W Cullinane / Yuko Saito / Tatiana Foroud / Thomas T Warner / ...Authors: Yang Yang / Yang Shi / Manuel Schweighauser / Xianjun Zhang / Abhay Kotecha / Alexey G Murzin / Holly J Garringer / Patrick W Cullinane / Yuko Saito / Tatiana Foroud / Thomas T Warner / Kazuko Hasegawa / Ruben Vidal / Shigeo Murayama / Tamas Revesz / Bernardino Ghetti / Masato Hasegawa / Tammaryn Lashley / Sjors H W Scheres / Michel Goedert / Abstract: Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. Neuropathologically, it is characterized by ...Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease. | |||||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_15285.map.gz | 25.6 MB | EMDB map data format | |
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Header (meta data) | emd-15285-v30.xml emd-15285.xml | 17.6 KB 17.6 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_15285_fsc.xml | 9.1 KB | Display | FSC data file |
Images | emd_15285.png | 91.6 KB | ||
Masks | emd_15285_msk_1.map | 64 MB | Mask map | |
Others | emd_15285_half_map_1.map.gz emd_15285_half_map_2.map.gz | 25.5 MB 25.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-15285 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-15285 | HTTPS FTP |
-Related structure data
Related structure data | 8a9lMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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-Map
File | Download / File: emd_15285.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.727 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_15285_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_15285_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_15285_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Alpha-synuclein filaments extracted from the human brain with PD,...
Entire | Name: Alpha-synuclein filaments extracted from the human brain with PD, PDD, and DLB |
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Components |
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-Supramolecule #1: Alpha-synuclein filaments extracted from the human brain with PD,...
Supramolecule | Name: Alpha-synuclein filaments extracted from the human brain with PD, PDD, and DLB type: tissue / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Alpha-synuclein
Macromolecule | Name: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: human (human) |
Molecular weight | Theoretical: 14.476108 KDa |
Sequence | String: MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A |
-Macromolecule #2: Unknown fragment
Macromolecule | Name: Unknown fragment / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 783.958 Da |
Sequence | String: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) |
-Macromolecule #3: Unknown fragment
Macromolecule | Name: Unknown fragment / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 627.775 Da |
Sequence | String: (UNK)(UNK)(UNK)(UNK)V(UNK)(UNK) |
-Macromolecule #4: water
Macromolecule | Name: water / type: ligand / ID: 4 / Number of copies: 6 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 0.6 µm |
Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |