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- EMDB-15371: Lipidic alpha-synuclein fibril - polymorph L1B -

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Basic information

Entry
Database: EMDB / ID: EMD-15371
TitleLipidic alpha-synuclein fibril - polymorph L1B
Map dataLipidic alpha-synuclein fibril - polymorph L1B
Sample
  • Complex: Lipidic alpha-synuclein fibril - polymorph L1B
    • 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 / dopamine uptake involved in synaptic transmission / synaptic vesicle transport / 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 / supramolecular fiber organization / phospholipid metabolic process / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / axon terminus / response to interleukin-1 / 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 / regulation of long-term neuronal synaptic plasticity / synapse organization / phospholipid binding / 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: 2.98 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
DepositionJul 11, 2022-
Header (metadata) releaseOct 12, 2022-
Map releaseOct 12, 2022-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15371.png

Downloads & links

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Map

FileDownload / File: emd_15371.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLipidic alpha-synuclein fibril - polymorph L1B
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: 0.06
Minimum - Maximum-0.08080832 - 0.1899721
Average (Standard dev.)0.0019825383 (±0.012888686)
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 fibril - polymorph L1B (half map 1)

Fileemd_15371_half_map_1.map
AnnotationLipidic alpha-synuclein fibril - polymorph L1B (half map 1)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Lipidic alpha-synuclein fibril - polymorph L1B (half map 2)

Fileemd_15371_half_map_2.map
AnnotationLipidic alpha-synuclein fibril - polymorph L1B (half map 2)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Lipidic alpha-synuclein fibril - polymorph L1B

EntireName: Lipidic alpha-synuclein fibril - polymorph L1B
Components
  • Complex: Lipidic alpha-synuclein fibril - polymorph L1B
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Lipidic alpha-synuclein fibril - polymorph L1B

SupramoleculeName: Lipidic alpha-synuclein fibril - polymorph L1B / 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: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
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: 50.83 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: 2.37 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.49 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 19108
Startup modelType of model: OTHER
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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