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- EMDB-52458: In vitro grown K58N Alpha-Synuclein Fibrils -

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Basic information

Entry
Database: EMDB / ID: EMD-52458
TitleIn vitro grown K58N Alpha-Synuclein Fibrils
Map dataPostprocessed K58N map
Sample
  • Organelle or cellular component: Alpha-Synuclein K58N
    • Protein or peptide: Alpha-synuclein
KeywordsAlpha-Synuclein / K58N Mutation / Fibrils / Cryo-EM / Protein Aggregation / Amyloid Structure / 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 / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization ...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 / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of norepinephrine uptake / transporter regulator activity / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / negative regulation of microtubule polymerization / synaptic vesicle transport / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / dynein complex binding / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of exocytosis / response to magnesium ion / synaptic vesicle exocytosis / enzyme inhibitor activity / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / regulation of presynapse assembly / response to type II interferon / alpha-tubulin binding / supramolecular fiber organization / inclusion body / phospholipid metabolic process / cellular response to copper ion / axon terminus / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / negative regulation of protein kinase activity / excitatory postsynaptic potential / fatty acid metabolic process / phosphoprotein binding / protein tetramerization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / protein destabilization / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / neuron apoptotic process / chemical synaptic transmission / molecular adaptor activity / negative regulation of neuron apoptotic process / response to lipopolysaccharide / histone binding / amyloid fibril formation / lysosome / oxidoreductase activity / transcription cis-regulatory region binding / postsynapse / positive regulation of apoptotic process / Amyloid fiber formation / copper ion binding / response to xenobiotic stimulus / axon / neuronal cell body
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsSicking K / Al-Azzani M / Outeiro TF / Fernandez-Busnadiego R
Funding support Germany, United States, 5 items
OrganizationGrant numberCountry
German Research Foundation (DFG)EXC 2067/1-390729940 Germany
German Research Foundation (DFG)SFB1286 (B8) Germany
German Research Foundation (DFG)SFB1286 (A12) Germany
German Research Foundation (DFG)448415290 Germany
Michael J. Fox FoundationASAP-000282 United States
CitationJournal: medRxiv / Year: 2025
Title: A novel alpha-synuclein K58N missense variant in a patient with Parkinson's disease.
Authors: Mohammed Al-Azzani / Sandrina Weber / Nagendran Ramalingam / Maria Ramón / Liana Shvachiy / Gonçalo Mestre / Michael Zech / Kevin Sicking / Alain Ibáñez de Opakua / Vidyashree Jayanthi / ...Authors: Mohammed Al-Azzani / Sandrina Weber / Nagendran Ramalingam / Maria Ramón / Liana Shvachiy / Gonçalo Mestre / Michael Zech / Kevin Sicking / Alain Ibáñez de Opakua / Vidyashree Jayanthi / Leslie Amaral / Aishwarya Agarwal / Aswathy Chandran / Susana R Chaves / Juliane Winkelmann / Claudia Trenkwalder / Maike Schwager / Silke Pauli / Ulf Dettmer / Claudio O Fernández / Janin Lautenschläger / Markus Zweckstetter / Ruben Fernandez Busnadiego / Brit Mollenhauer / Tiago Fleming Outeiro /
Abstract: Mutations and multiplications in the SNCA , encoding alpha-synuclein (aSyn), are associated with familial forms of Parkinson's disease (PD). We report the identification of a novel missense mutation ...Mutations and multiplications in the SNCA , encoding alpha-synuclein (aSyn), are associated with familial forms of Parkinson's disease (PD). We report the identification of a novel missense mutation (NM_000345.4, cDNA 174G>C; protein K58N) in a PD patient using whole exome sequencing, and describe comprehensive molecular and cellular analysss of the effects of this novel mutation. The patient exhibited typical sporadic PD with early onset and a benign disease course. Biophysical studies revealed that the K58N substitution causes local structural effects, disrupts binding to membranes, and enhances aSyn in vitro aggregation. K58N aSyn produces fewer inclusions per cell, and fails to undergo condensate formation. The mutation increases the cytoplasmic distribution of the protein, and has minimal effect on the dynamic reversibility of serine-129 phosphorylation. In total, the identification of this novel mutation advances our understanding of aSyn biology and pathobiology.
History
DepositionJan 7, 2025-
Header (metadata) releaseFeb 12, 2025-
Map releaseFeb 12, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52458.png

Downloads & links

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Map

FileDownload / File: emd_52458.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPostprocessed K58N map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.92 Å/pix.
x 384 pix.
= 353.28 Å		0.92 Å/pix.
x 384 pix.
= 353.28 Å		0.92 Å/pix.
x 384 pix.
= 353.28 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.92 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.042952515 - 0.049188357
Average (Standard dev.)0.000016287006 (±0.0024524885)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 353.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Second half map

Fileemd_52458_half_map_1.map
AnnotationSecond half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: First half map

Fileemd_52458_half_map_2.map
AnnotationFirst half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Alpha-Synuclein K58N

EntireName: Alpha-Synuclein K58N
Components
  • Organelle or cellular component: Alpha-Synuclein K58N
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Alpha-Synuclein K58N

SupramoleculeName: Alpha-Synuclein K58N / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.46 kDa/nm

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.461032 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAENTK 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
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: Featureless cylinder
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 22995
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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