+
Open data
-
Basic information
Entry | ![]() | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | Lipidic alpha-synuclein fibril - polymorph L3A | |||||||||||||||
![]() | Lipidic alpha-synuclein fibril - polymorph L3A | |||||||||||||||
![]() |
| |||||||||||||||
Function / homology | ![]() negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of phospholipase activity / negative regulation of monooxygenase activity / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of phospholipase activity / negative regulation of monooxygenase activity / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / negative regulation of transporter activity / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / regulation of synaptic vesicle recycling / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / regulation of norepinephrine uptake / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of macrophage activation / negative regulation of microtubule polymerization / dopamine uptake involved in synaptic transmission / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / positive regulation of exocytosis / synaptic vesicle exocytosis / kinesin binding / positive regulation of endocytosis / mitochondrial ATP synthesis coupled electron transport / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / alpha-tubulin binding / localization / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / Hsp70 protein binding / cellular response to epinephrine stimulus / excitatory postsynaptic potential / response to interleukin-1 / adult locomotory behavior / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / fatty acid metabolic process / long-term synaptic potentiation / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / protein destabilization / ferrous iron binding / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / PKR-mediated signaling / tau protein binding / positive regulation of protein serine/threonine kinase activity / receptor internalization / phospholipid binding / synaptic vesicle membrane / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / actin binding / cell cortex / histone binding / cellular response to oxidative stress / growth cone / postsynapse / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / molecular adaptor activity / oxidoreductase activity / lysosome / transcription cis-regulatory region binding Similarity search - Function | |||||||||||||||
Biological species | ![]() | |||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.76 Å | |||||||||||||||
![]() | Frieg B / Antonschmidt L / Dienemann C / Geraets JA / Najbauer EE / Matthes D / de Groot BL / Andreas LB / Becker S / Griesinger C / Schroeder GF | |||||||||||||||
Funding support | ![]()
| |||||||||||||||
![]() | ![]() 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 |
|
-
Structure visualization
Supplemental images |
---|
-
Downloads & links
-EMDB archive
Map data | ![]() | 8.9 MB | ![]() | |
---|---|---|---|---|
Header (meta data) | ![]() ![]() | 15.3 KB 15.3 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 8.9 KB | Display | ![]() |
Images | ![]() | 51.6 KB | ||
Others | ![]() ![]() | 46 MB 46 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 659.8 KB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 659.4 KB | Display | |
Data in XML | ![]() | 14.6 KB | Display | |
Data in CIF | ![]() | 20.5 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8aexMC ![]() 8a4lC ![]() 8adsC ![]() 8aduC ![]() 8advC ![]() 8adwC C: citing same article ( M: atomic model generated by this map |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
EMDB pages | ![]() ![]() |
---|
-
Map
File | ![]() | ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Lipidic alpha-synuclein fibril - polymorph L3A | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.05 Å | ||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Half map: Lipidic alpha-synuclein fibril - polymorph L3A (half map 1)
File | emd_15388_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Lipidic alpha-synuclein fibril - polymorph L3A (half map 1) | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: Lipidic alpha-synuclein fibril - polymorph L3A (half map 2)
File | emd_15388_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Lipidic alpha-synuclein fibril - polymorph L3A (half map 2) | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-
Sample components
-Entire : Lipidic alpha-synuclein fibril - polymorph L3A
Entire | Name: Lipidic alpha-synuclein fibril - polymorph L3A |
---|---|
Components |
|
-Supramolecule #1: Lipidic alpha-synuclein fibril - polymorph L3A
Supramolecule | Name: Lipidic alpha-synuclein fibril - polymorph L3A / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all |
---|---|
Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: Alpha-synuclein
Macromolecule | Name: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 14.476108 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
![]() | helical reconstruction |
Aggregation state | filament |
-
Sample preparation
Buffer | pH: 7.4 |
---|---|
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 42.72 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination 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 |