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- EMDB-30648: Cryo-EM structure of the hE46K cross-seeded mWT alpha-synuclein fibril -

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Basic information

Entry
Database: EMDB / ID: EMD-30648
TitleCryo-EM structure of the hE46K cross-seeded mWT alpha-synuclein fibril
Map data
Sample
  • Organelle or cellular component: the hE46K cross-seeded mWT alpha-synuclein fibril
    • Protein or peptide: Alpha-synuclein
Function / homology
Function and homology information


response to desipramine / : / : / : / : / : / response to xenobiotic stimulus => GO:0009410 / : / regulation of neurotransmitter secretion / negative regulation of dopamine metabolic process ...response to desipramine / : / : / : / : / : / response to xenobiotic stimulus => GO:0009410 / : / regulation of neurotransmitter secretion / negative regulation of dopamine metabolic process / membrane organization / synaptic transmission, dopaminergic / 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 / nuclear outer membrane / cellular response to fibroblast growth factor stimulus / 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 / regulation of reactive oxygen species metabolic process / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / arachidonic acid binding / 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 / dynein complex binding / positive regulation of receptor recycling / dopamine metabolic process / regulation of dopamine secretion / beta-tubulin binding / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / regulation of neuronal synaptic plasticity / synaptic vesicle exocytosis / positive regulation of exocytosis / kinesin binding / positive regulation of endocytosis / mitochondrial ATP synthesis coupled electron transport / phospholipase binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / behavioral response to cocaine / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / alpha-tubulin binding / positive regulation of synaptic transmission / phospholipid metabolic process / axon terminus / rough endoplasmic reticulum / inclusion body / cellular response to copper ion / 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 / negative regulation of protein phosphorylation / 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 / protein destabilization / cytoplasmic vesicle membrane / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / ferrous iron binding / tau protein binding / positive regulation of protein serine/threonine kinase activity / mitochondrial intermembrane space / terminal bouton / receptor internalization / phospholipid binding / synaptic vesicle membrane / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
Methodhelical reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsLong HF / Sun YP / Liu C
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding.
Authors: Houfang Long / Weitong Zheng / Yang Liu / Yunpeng Sun / Kun Zhao / Zhenying Liu / Wencheng Xia / Shiran Lv / Zhengtao Liu / Dan Li / Kai-Wen He / Cong Liu /
Abstract: Heterozygous point mutations of α-synuclein (α-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary ...Heterozygous point mutations of α-synuclein (α-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) α-syn and its role in the exacerbated pathology of α-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant α-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different α-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryo-electron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT α-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT α-syn in such a way that the mutant pathology would be amplified in fPD.
History
DepositionOct 28, 2020-
Header (metadata) releaseNov 3, 2021-
Map releaseNov 3, 2021-
UpdateMay 18, 2022-
Current statusMay 18, 2022Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.00877
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.00877
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30648.png

Downloads & links

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Map

FileDownload / File: emd_30648.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.00877 / Movie #1: 0.00877
Minimum - Maximum-0.019819198 - 0.04151593
Average (Standard dev.)0.0002823448 (±0.0020141404)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 305.27997 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z305.280305.280305.280
α/β/γ90.00090.00090.000
start NX/NY/NZ149141182
NX/NY/NZ215231150
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-0.0200.0420.000

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Supplemental data

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Sample components

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Entire : the hE46K cross-seeded mWT alpha-synuclein fibril

EntireName: the hE46K cross-seeded mWT alpha-synuclein fibril
Components
  • Organelle or cellular component: the hE46K cross-seeded mWT alpha-synuclein fibril
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: the hE46K cross-seeded mWT alpha-synuclein fibril

SupramoleculeName: the hE46K cross-seeded mWT alpha-synuclein fibril / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVTTVAEKTK EQVTNVGGA VVTGVTAVAQ KTVEGAGNIA AATGFVKKDQ MGKGEEGYPQ EGILEDMPVD P GSEAYEMP SEEGYQDYEP EA

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 35.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.42 Å
Applied symmetry - Helical parameters - Δ&Phi: -179.55 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 7466
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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