+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-15148 | |||||||||||||||
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Title | Lipidic alpha-synuclein fibril - polymorph L2A | |||||||||||||||
Map data | half map 1 lipidic alpha-synuclein polymorph L2A | |||||||||||||||
Sample |
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Keywords | amyloid fibril / 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 / response to iron(II) ion / regulation of norepinephrine uptake / 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 / synaptic vesicle transport / dopamine uptake involved in synaptic transmission / dynein complex binding / regulation of dopamine secretion / positive regulation of receptor recycling / 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 / positive regulation of endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / synaptic vesicle endocytosis / regulation of presynapse assembly / negative regulation of serotonin uptake / alpha-tubulin binding / phospholipid metabolic process / supramolecular fiber organization / axon terminus / mitochondrial ATP synthesis coupled electron transport / inclusion body / fatty acid metabolic process / cellular response to copper ion / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / adult locomotory behavior / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / excitatory postsynaptic potential / long-term synaptic potentiation / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / synapse organization / microglial cell activation / negative regulation of protein kinase activity / regulation of long-term neuronal synaptic plasticity / protein destabilization / ferrous iron binding / tau protein binding / positive regulation of protein serine/threonine kinase activity / PKR-mediated signaling / receptor internalization / phospholipid binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / synaptic vesicle membrane / positive regulation of inflammatory response / positive regulation of peptidyl-serine phosphorylation / actin cytoskeleton / actin binding / cellular response to oxidative stress / histone binding / cell cortex / growth cone / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / transcription cis-regulatory region binding / postsynapse / amyloid fibril formation / response to lipopolysaccharide / molecular adaptor activity / oxidoreductase activity / lysosome / response to xenobiotic stimulus Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.68 Å | |||||||||||||||
Authors | Frieg B / Antonschmidt L / Dienemann C / Geraets JA / Najbauer EE / Matthes D / de Groot BL / Andreas LB / Becker S / Griesinger C / Schroeder GF | |||||||||||||||
Funding support | Germany, 4 items
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Citation | Journal: Nat Commun / Year: 2022 Title: The 3D structure of lipidic fibrils of α-synuclein. Authors: Benedikt Frieg / Leif Antonschmidt / Christian Dienemann / James A Geraets / Eszter E Najbauer / Dirk Matthes / Bert L de Groot / Loren B Andreas / Stefan Becker / Christian Griesinger / Gunnar F Schröder / Abstract: α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson's disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal ...α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson's disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal inclusions called Lewy bodies. Studies on the composition of Lewy bodies extracted postmortem from brain tissue of Parkinson's patients revealed that lipids and membranous organelles are also a significant component. Interactions between α-synuclein and lipids have been previously identified as relevant for Parkinson's disease pathology, however molecular insights into their interactions have remained elusive. Here we present cryo-electron microscopy structures of six α-synuclein fibrils in complex with lipids, revealing specific lipid-fibril interactions. We observe that phospholipids promote an alternative protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities of the fibrils. Together with our previous studies, these structures also indicate a mechanism for fibril-induced lipid extraction, which is likely to be involved in the development of α-synucleinopathies. Specifically, one potential mechanism for the cellular toxicity is the disruption of intracellular vesicles mediated by fibrils and oligomers, and therefore the modulation of these interactions may provide a promising strategy for future therapeutic interventions. | |||||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_15148.map.gz | 13.5 MB | EMDB map data format | |
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Header (meta data) | emd-15148-v30.xml emd-15148.xml | 14.5 KB 14.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_15148_fsc.xml | 8.9 KB | Display | FSC data file |
Images | emd_15148.png | 59.8 KB | ||
Filedesc metadata | emd-15148.cif.gz | 5.1 KB | ||
Others | emd_15148_half_map_1.map.gz emd_15148_half_map_2.map.gz | 46.2 MB 46.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-15148 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-15148 | HTTPS FTP |
-Validation report
Summary document | emd_15148_validation.pdf.gz | 875.8 KB | Display | EMDB validaton report |
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Full document | emd_15148_full_validation.pdf.gz | 875.4 KB | Display | |
Data in XML | emd_15148_validation.xml.gz | 14.5 KB | Display | |
Data in CIF | emd_15148_validation.cif.gz | 20.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-15148 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-15148 | HTTPS FTP |
-Related structure data
Related structure data | 8a4lMC 8adsC 8aduC 8advC 8adwC 8aexC 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_15148.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | half map 1 lipidic alpha-synuclein polymorph L2A | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.05 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: lipidic alpha-synuclein polymorph L2A
File | emd_15148_half_map_1.map | ||||||||||||
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Annotation | lipidic alpha-synuclein polymorph L2A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half map 2 lipidic alpha-synuclein polymorph L2A
File | emd_15148_half_map_2.map | ||||||||||||
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Annotation | half map 2 lipidic alpha-synuclein polymorph L2A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : amyloid fibril of alpha-synuclein
Entire | Name: amyloid fibril of alpha-synuclein |
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Components |
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-Supramolecule #1: amyloid fibril of alpha-synuclein
Supramolecule | Name: amyloid fibril of alpha-synuclein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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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: 15 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 14.476108 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
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: 7.4 |
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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: 50.0 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: 2.0 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |