+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-17111 | |||||||||
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Title | Cryo-EM structure of the wild-type alpha-synuclein fibril. | |||||||||
Map data | Cryo-EM structure of the wild-type alpha-synuclein fibril. | |||||||||
Sample |
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Keywords | alpha-synuclein / amyloid / fibril / Parkinson's disease / PROTEIN FIBRIL | |||||||||
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 / 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 / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of macrophage activation / negative regulation of microtubule polymerization / dopamine uptake involved in synaptic transmission / 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 / synaptic vesicle exocytosis / positive regulation of 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 / cellular response to epinephrine stimulus / Hsp70 protein binding / 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 / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / negative regulation of protein kinase activity / protein destabilization / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / ferrous iron binding / tau protein binding / PKR-mediated signaling / 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 / histone binding / cellular response to oxidative stress / 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 | Homo sapiens (human) | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||
Authors | Pesch V / Reithofer S / Ma L / Flores-Fernandez JM / Oezduezenciler P / Busch Y / Lien Y / Rudtke O / Frieg B / Schroeder GF ...Pesch V / Reithofer S / Ma L / Flores-Fernandez JM / Oezduezenciler P / Busch Y / Lien Y / Rudtke O / Frieg B / Schroeder GF / Wille H / Tamgueney G | |||||||||
Funding support | United States, Germany, 2 items
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Citation | Journal: Brain / Year: 2024 Title: Vaccination with structurally adapted fungal protein fibrils induces immunity to Parkinson's disease. Authors: Verena Pesch / José Miguel Flores-Fernandez / Sara Reithofer / Liang Ma / Pelin Özdüzenciler / Yannick Busch / Aishwarya Sriraman / YongLiang Wang / Sara Amidian / Chiara V M Kroepel / ...Authors: Verena Pesch / José Miguel Flores-Fernandez / Sara Reithofer / Liang Ma / Pelin Özdüzenciler / Yannick Busch / Aishwarya Sriraman / YongLiang Wang / Sara Amidian / Chiara V M Kroepel / Laura Müller / Yi Lien / Olivia Rudtke / Benedikt Frieg / Gunnar F Schröder / Holger Wille / Gültekin Tamgüney / Abstract: The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, a progressive age-related neurodegenerative disease ...The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, a progressive age-related neurodegenerative disease for which there is no cure. HET-s is a soluble fungal protein that can form assembled amyloid fibrils in its prion state. We engineered HET-s(218-298) to form four different fibrillar vaccine candidates, each displaying a specific conformational epitope present on the surface of α-synuclein fibrils. Vaccination with these four vaccine candidates prolonged the survival of immunized TgM83+/- mice challenged with α-synuclein fibrils by 8% when injected into the brain to model brain-first Parkinson's disease or by 21% and 22% when injected into the peritoneum or gut wall, respectively, to model body-first Parkinson's disease. Antibodies from fully immunized mice recognized α-synuclein fibrils and brain homogenates from patients with Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Conformation-specific vaccines that mimic epitopes present only on the surface of pathological fibrils but not on soluble monomers, hold great promise for protection against Parkinson's disease, related synucleinopathies and other amyloidogenic protein misfolding disorders. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_17111.map.gz | 8.5 MB | EMDB map data format | |
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Header (meta data) | emd-17111-v30.xml emd-17111.xml | 14.8 KB 14.8 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_17111_fsc.xml | 8.9 KB | Display | FSC data file |
Images | emd_17111.png | 48.5 KB | ||
Filedesc metadata | emd-17111.cif.gz | 5.3 KB | ||
Others | emd_17111_half_map_1.map.gz emd_17111_half_map_2.map.gz | 46.2 MB 46.2 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-17111 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-17111 | HTTPS FTP |
-Validation report
Summary document | emd_17111_validation.pdf.gz | 803.9 KB | Display | EMDB validaton report |
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Full document | emd_17111_full_validation.pdf.gz | 803.4 KB | Display | |
Data in XML | emd_17111_validation.xml.gz | 14.7 KB | Display | |
Data in CIF | emd_17111_validation.cif.gz | 20.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-17111 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-17111 | HTTPS FTP |
-Related structure data
Related structure data | 8oqiMC 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_17111.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Cryo-EM structure of the wild-type alpha-synuclein fibril. | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.06 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Cryo-EM structure of the wild-type alpha-synuclein fibril (half...
File | emd_17111_half_map_1.map | ||||||||||||
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Annotation | Cryo-EM structure of the wild-type alpha-synuclein fibril (half map 2). | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Cryo-EM structure of the wild-type alpha-synuclein fibril (half...
File | emd_17111_half_map_2.map | ||||||||||||
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Annotation | Cryo-EM structure of the wild-type alpha-synuclein fibril (half map 1). | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Human wild-type alpha-synuclein fibril
Entire | Name: Human wild-type alpha-synuclein fibril |
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Components |
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-Supramolecule #1: Human wild-type alpha-synuclein fibril
Supramolecule | Name: Human wild-type alpha-synuclein fibril / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all Details: N-terminally acetylated human wild-type alpha-synuclein |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Alpha-synuclein
Macromolecule | Name: Alpha-synuclein / type: protein_or_peptide / ID: 1 Details: N-terminally acetylated human wild-type alpha-synuclein. Number of copies: 10 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 14.476108 KDa |
Recombinant expression | Organism: Escherichia coli BL21(DE3) (bacteria) |
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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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Buffer | pH: 7.2 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 30.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |