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- EMDB-15148: Lipidic alpha-synuclein fibril - polymorph L2A -

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Basic information

Entry
Database: EMDB / ID: EMD-15148
TitleLipidic alpha-synuclein fibril - polymorph L2A
Map datahalf map 1 lipidic alpha-synuclein polymorph L2A
Sample
  • Complex: amyloid fibril of alpha-synuclein
    • Protein or peptide: Alpha-synuclein
Keywordsamyloid fibril / PROTEIN FIBRIL
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 / negative regulation of exocytosis / dopamine biosynthetic process / dopamine uptake involved in synaptic transmission / response to iron(II) ion / 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 / negative regulation of microtubule polymerization / synaptic vesicle priming / regulation of norepinephrine uptake / transporter regulator activity / protein kinase inhibitor activity / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle transport / regulation of dopamine secretion / positive regulation of receptor recycling / cuprous ion binding / positive regulation of exocytosis / nuclear outer membrane / dynein complex binding / synaptic transmission, dopaminergic / synaptic vesicle exocytosis / response to magnesium ion / positive regulation of endocytosis / negative regulation of serotonin uptake / kinesin binding / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / cellular response to fibroblast growth factor stimulus / response to type II interferon / cellular response to epinephrine stimulus / inclusion body / Hsp70 protein binding / response to interleukin-1 / axon terminus / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / enzyme inhibitor activity / regulation of microtubule cytoskeleton organization / SNARE binding / glutathione metabolic process / protein tetramerization / protein sequestering activity / phosphoprotein binding / receptor internalization / tubulin binding / microglial cell activation / ferrous iron binding / phospholipid binding / PKR-mediated signaling / synapse organization / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / actin cytoskeleton / synaptic vesicle membrane / growth cone / actin binding / cellular response to oxidative stress / response to lipopolysaccharide / histone binding / cell cortex / microtubule binding / amyloid fibril formation / negative regulation of neuron apoptotic process / mitochondrial outer membrane / lysosome / oxidoreductase activity / mitochondrial inner membrane / transcription cis-regulatory region binding / positive regulation of apoptotic process / ribosome / mitochondrial matrix / Amyloid fiber formation / copper ion binding / protein domain specific binding / axon / neuronal cell body / calcium ion binding
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.68 Å
AuthorsFrieg B / Antonschmidt L / Dienemann C / Geraets JA / Najbauer EE / Matthes D / de Groot BL / Andreas LB / Becker S / Griesinger C / Schroeder GF
Funding support Germany, 4 items
OrganizationGrant numberCountry
Max Planck Society Germany
German Research Foundation (DFG)2067/1-390729940 Germany
German Research Foundation (DFG)397022504 Germany
Helmholtz Association Germany
CitationJournal: Nat Commun / Year: 2022
Title: The 3D structure of lipidic fibrils of α-synuclein.
Authors: Benedikt Frieg / Leif Antonschmidt / Christian Dienemann / James A Geraets / Eszter E Najbauer / Dirk Matthes / Bert L de Groot / Loren B Andreas / Stefan Becker / Christian Griesinger / Gunnar F Schröder /
Abstract: α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson's disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal ...α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson's disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal inclusions called Lewy bodies. Studies on the composition of Lewy bodies extracted postmortem from brain tissue of Parkinson's patients revealed that lipids and membranous organelles are also a significant component. Interactions between α-synuclein and lipids have been previously identified as relevant for Parkinson's disease pathology, however molecular insights into their interactions have remained elusive. Here we present cryo-electron microscopy structures of six α-synuclein fibrils in complex with lipids, revealing specific lipid-fibril interactions. We observe that phospholipids promote an alternative protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities of the fibrils. Together with our previous studies, these structures also indicate a mechanism for fibril-induced lipid extraction, which is likely to be involved in the development of α-synucleinopathies. Specifically, one potential mechanism for the cellular toxicity is the disruption of intracellular vesicles mediated by fibrils and oligomers, and therefore the modulation of these interactions may provide a promising strategy for future therapeutic interventions.
History
DepositionJun 12, 2022-
Header (metadata) releaseAug 17, 2022-
Map releaseAug 17, 2022-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15148.png

Downloads & links

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Map

FileDownload / File: emd_15148.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhalf map 1 lipidic alpha-synuclein polymorph L2A
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 250 pix.
= 262.5 Å		1.05 Å/pix.
x 250 pix.
= 262.5 Å		1.05 Å/pix.
x 250 pix.
= 262.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.10766372 - 0.24158762
Average (Standard dev.)0.0018886091 (±0.014961117)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions250250250
Spacing250250250
CellA=B=C: 262.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: lipidic alpha-synuclein polymorph L2A

Fileemd_15148_half_map_1.map
Annotationlipidic alpha-synuclein polymorph L2A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2 lipidic alpha-synuclein polymorph L2A

Fileemd_15148_half_map_2.map
Annotationhalf map 2 lipidic alpha-synuclein polymorph L2A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : amyloid fibril of alpha-synuclein

EntireName: amyloid fibril of alpha-synuclein
Components
  • Complex: amyloid fibril of alpha-synuclein
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: amyloid fibril of alpha-synuclein

SupramoleculeName: amyloid fibril of alpha-synuclein / type: complex / 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: 15 / 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 K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.68 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.75 °
Applied symmetry - Helical parameters - Axial symmetry: C3 (3 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 2.68 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 46003
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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