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- EMDB-50023: mouse alpha-synuclein -

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Basic information

Entry
Database: EMDB / ID: EMD-50023
Titlemouse alpha-synuclein
Map data
Sample
  • Complex: Mouse alpha-synuclein fibrils
    • Protein or peptide: Alpha-synuclein
Keywordsalpha-synuclein / recombinant / fibril / PROTEIN FIBRIL
Function / homology
Function and homology information


PKR-mediated signaling / regulation of neurotransmitter secretion / platelet alpha granule membrane / membrane organization / synaptic transmission, dopaminergic / neurotransmitter secretion / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake ...PKR-mediated signaling / regulation of neurotransmitter secretion / platelet alpha granule membrane / membrane organization / synaptic transmission, dopaminergic / neurotransmitter secretion / 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 / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / arachidonate binding / regulation of glutamate secretion / regulation of reactive oxygen species metabolic process / dopamine biosynthetic process / SNARE complex assembly / response to iron(II) ion / positive regulation of neurotransmitter secretion / positive regulation of inositol phosphate biosynthetic process / regulation of locomotion / negative regulation of dopamine metabolic process / regulation of macrophage activation / transporter regulator activity / negative regulation of microtubule polymerization / synaptic vesicle transport / synaptic vesicle priming / mitochondrial ATP synthesis coupled electron transport / regulation of dopamine secretion / dynein complex binding / positive regulation of receptor recycling / negative regulation of thrombin-activated receptor signaling pathway / dopamine metabolic process / cuprous ion binding / nuclear outer membrane / protein complex oligomerization / response to magnesium ion / positive regulation of endocytosis / positive regulation of exocytosis / kinesin binding / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / regulation of neuronal synaptic plasticity / response to type II interferon / regulation of presynapse assembly / alpha-tubulin binding / positive regulation of synaptic transmission / beta-tubulin binding / behavioral response to cocaine / phospholipase binding / phospholipid metabolic process / cellular response to fibroblast growth factor stimulus / inclusion body / axon terminus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / adult locomotory behavior / excitatory postsynaptic potential / phosphoprotein binding / protein tetramerization / microglial cell activation / fatty acid metabolic process / ferrous iron binding / regulation of long-term neuronal synaptic plasticity / synapse organization / protein destabilization / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / terminal bouton / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / chemical synaptic transmission / mitochondrial outer membrane / negative regulation of neuron apoptotic process / cytoskeleton / oxidoreductase activity / postsynapse
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
Methodhelical reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsTatli M / Stahlberg H / Kolla R / Nazarov S / Weil MT / Schondorf DC / Geist D / Reinhardt P / Ehrnhoefer DE / Gasparini L / Lashuel HA
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation310030_188548 Switzerland
CitationJournal: Sci Adv / Year: 2024
Title: Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases.
Authors: Arpine Sokratian / Ye Zhou / Meltem Tatli / Kevin J Burbidge / Enquan Xu / Elizabeth Viverette / Sonia Donzelli / Addison M Duda / Yuan Yuan / Huizhong Li / Samuel Strader / Nirali Patel / ...Authors: Arpine Sokratian / Ye Zhou / Meltem Tatli / Kevin J Burbidge / Enquan Xu / Elizabeth Viverette / Sonia Donzelli / Addison M Duda / Yuan Yuan / Huizhong Li / Samuel Strader / Nirali Patel / Lauren Shiell / Tuyana Malankhanova / Olivia Chen / Joseph R Mazzulli / Lalith Perera / Henning Stahlberg / Mario Borgnia / Alberto Bartesaghi / Hilal A Lashuel / Andrew B West /
Abstract: The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson's disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in ...The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson's disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here, we report the first atomic structure of mouse α-synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse α-synuclein fibrils display altered packing arrangements, reduced hydrophobicity, and heightened fragmentation sensitivity and evoke only weak immunological responses. Furthermore, mouse α-synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized α-synuclein mice. These findings provide critical insights into the structural underpinnings of α-synuclein pathogenicity and emphasize a need to reassess the role of mouse α-synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.
History
DepositionApr 4, 2024-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_50023.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.88 Å/pix.
x 360 pix.
= 316.08 Å
0.88 Å/pix.
x 360 pix.
= 316.08 Å
0.88 Å/pix.
x 360 pix.
= 316.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.878 Å
Density
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.046285026 - 0.074209444
Average (Standard dev.)0.000045150515 (±0.0012261672)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 316.08002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50023_msk_1.map
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AxesZYX

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Additional map: #1

Fileemd_50023_additional_1.map
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Half map: #2

Fileemd_50023_half_map_1.map
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Half map: #1

Fileemd_50023_half_map_2.map
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Sample components

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Entire : Mouse alpha-synuclein fibrils

EntireName: Mouse alpha-synuclein fibrils
Components
  • Complex: Mouse alpha-synuclein fibrils
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Mouse alpha-synuclein fibrils

SupramoleculeName: Mouse alpha-synuclein fibrils / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 10 kDa/nm

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 14.501185 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVTTVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGNIA AATGFVKKDQ MGKGEEGYPQ EGILEDMPVD PGSEAYEMPS 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
Component:
ConcentrationFormulaName
137.0 mMNaClsodium chloride
2.7 mMKClpotasium chloride
10.0 mMNa2HPODisodium phosphate
1.8 mMKH2PO4Monopotassium phosphate
GridModel: Quantifoil / Support film - Material: CARBON
VitrificationCryogen name: ETHANE
Detailsin PBS, sonicated sample

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 5358 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.39 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.6 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 50378
Segment selectionNumber selected: 146075
Startup modelType of model: OTHER
Details: IniModel2D was used for the initial model creation.
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 51.895 / Target criteria: 0.759261
Output model

PDB-9ewv:
mouse alpha-synuclein

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