+Open data
-Basic information
Entry | Database: PDB / ID: 6l4s | ||||||
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Title | cryo-em structure of alpha-synuclein fiber mutation type E46K | ||||||
Components | Alpha-synuclein | ||||||
Keywords | PROTEIN FIBRIL / alpha-syn fiber / Parkinson disease | ||||||
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 / mitochondrial ATP synthesis coupled electron transport / 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 / inclusion body / 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 / fatty acid metabolic process / 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 / 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 / cellular response to oxidative stress / histone binding / cell cortex / growth cone / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / postsynapse / amyloid fibril formation / response to lipopolysaccharide / molecular adaptor activity / oxidoreductase activity / lysosome / transcription cis-regulatory region binding / response to xenobiotic stimulus Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.37 Å | ||||||
Authors | Li, Y.W. / Zhao, K. / Liu, C. / Li, X. | ||||||
Citation | Journal: Nat Commun / Year: 2020 Title: Parkinson's disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure. Authors: Kun Zhao / Yaowang Li / Zhenying Liu / Houfang Long / Chunyu Zhao / Feng Luo / Yunpeng Sun / Youqi Tao / Xiao-Dong Su / Dan Li / Xueming Li / Cong Liu / Abstract: Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson's disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of α-syn have been ...Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson's disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of α-syn have been identified causative to the early onset of familial PD. Here, we report the cryo-EM structure of an α-syn fibril formed by N-terminally acetylated E46K mutant α-syn (Ac-E46K). The fibril structure represents a distinct fold of α-syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) α-syn fibril and thus triggers the rearrangement of the overall structure. Furthermore, we show that the Ac-E46K fibril is less resistant to harsh conditions and protease cleavage, and more prone to be fragmented with an enhanced seeding capability than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of α-syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6l4s.cif.gz | 57.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6l4s.ent.gz | 43.8 KB | Display | PDB format |
PDBx/mmJSON format | 6l4s.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/l4/6l4s ftp://data.pdbj.org/pub/pdb/validation_reports/l4/6l4s | HTTPS FTP |
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-Related structure data
Related structure data | 0833MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 5402.157 Da / Num. of mol.: 6 / Mutation: E46K Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli K-12 (bacteria) / Strain (production host): K-12 / References: UniProt: P37840 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: alpha-synuclein fiber mutation type E46K / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli K-12 (bacteria) / Strain: K-12 |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 289 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Average exposure time: 8 sec. / Electron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
Image scans | Movie frames/image: 32 / Used frames/image: 1-32 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||
Helical symmerty | Angular rotation/subunit: 179.371 ° / Axial rise/subunit: 2.376 Å / Axial symmetry: C1 | ||||||||||||||||
3D reconstruction | Resolution: 3.37 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 18009 / Symmetry type: HELICAL |