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- EMDB-30269: Cryo-EM structure of the hE46K cross-seeded hWT alpha-synuclein fibril -

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Basic information

Entry
Database: EMDB / ID: EMD-30269
TitleCryo-EM structure of the hE46K cross-seeded hWT alpha-synuclein fibril
Map data
Sample
  • Organelle or cellular component: the hE46K cross-seeded hWT alpha-synuclein fibril
    • Protein or peptide: Alpha-synuclein
Keywordsamyloid fibril / PROTEIN FIBRIL
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / regulation of synaptic vesicle recycling ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / mitochondrial membrane organization / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / positive regulation of neurotransmitter secretion / regulation of macrophage activation / negative regulation of dopamine metabolic process / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of thrombin-activated receptor signaling pathway / Lewy body / regulation of locomotion / negative regulation of microtubule polymerization / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of norepinephrine uptake / transporter regulator activity / protein kinase inhibitor activity / synaptic vesicle transport / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / positive regulation of receptor recycling / positive regulation of exocytosis / cuprous ion binding / mitochondrial ATP synthesis coupled electron transport / nuclear outer membrane / dynein complex binding / response to magnesium ion / synaptic vesicle exocytosis / positive regulation of endocytosis / negative regulation of serotonin uptake / response to type II interferon / kinesin binding / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / phospholipid metabolic process / supramolecular fiber organization / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / response to interleukin-1 / axon terminus / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / regulation of microtubule cytoskeleton organization / SNARE binding / adult locomotory behavior / glutathione metabolic process / protein tetramerization / excitatory postsynaptic potential / protein sequestering activity / tubulin binding / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / receptor internalization / phospholipid binding / synapse organization / regulation of long-term neuronal synaptic plasticity / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / growth cone / actin binding / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / amyloid fibril formation / chemical synaptic transmission
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsSun YP / Zhao K
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
DepositionMay 3, 2020-
Header (metadata) releaseMay 5, 2021-
Map releaseMay 5, 2021-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0269
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0269
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7c1d
  • Surface level: 0.0269
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7c1d
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30269.png

Downloads & links

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Map

FileDownload / File: emd_30269.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.36 Å/pix.
x 224 pix.
= 303.744 Å		1.36 Å/pix.
x 224 pix.
= 303.744 Å		1.36 Å/pix.
x 224 pix.
= 303.744 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.356 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0269 / Movie #1: 0.0269
Minimum - Maximum-0.093736865 - 0.13635482
Average (Standard dev.)0.00066999916 (±0.004877077)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 303.744 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.3561.3561.356
M x/y/z224224224
origin x/y/z0.0000.0000.000
length x/y/z303.744303.744303.744
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS224224224
D min/max/mean-0.0940.1360.001

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Supplemental data

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Sample components

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

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

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

SupramoleculeName: the hE46K cross-seeded hWT alpha-synuclein fibril / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

UniProtKB: Alpha-synuclein

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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: -179.53 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 11867
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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