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- PDB-7nca: Type 1A alpha-synuclein filament seeded in vitro by filaments pur... -

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Basic information

Entry
Database: PDB / ID: 7nca
TitleType 1A alpha-synuclein filament seeded in vitro by filaments purified from Multiple Systems Atrophy Case 2
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / Amyloid / Multiple System Atrophy / Neurodegeneration / alpha-synuclein / filament
Function / homology
Function and homology information


regulation of phospholipase activity / negative regulation of monooxygenase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of glutathione peroxidase activity / 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 ...regulation of phospholipase activity / negative regulation of monooxygenase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of glutathione peroxidase activity / 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 / negative regulation of transporter activity / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / regulation of synaptic vesicle recycling / 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 / regulation of norepinephrine uptake / 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 / synaptic vesicle transport / dynein complex binding / dopamine uptake involved in synaptic transmission / positive regulation of receptor recycling / regulation of dopamine secretion / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / response to magnesium ion / response to type II interferon / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / mitochondrial ATP synthesis coupled electron transport / synaptic vesicle endocytosis / regulation of presynapse assembly / negative regulation of serotonin uptake / alpha-tubulin binding / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / : / adult locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / excitatory postsynaptic potential / fatty acid metabolic process / long-term synaptic potentiation / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / protein destabilization / negative regulation of protein kinase activity / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / positive regulation of protein serine/threonine kinase activity / tau protein binding / PKR-mediated signaling / receptor internalization / : / phospholipid binding / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / actin binding / cell cortex / cellular response to oxidative stress / histone binding / growth cone / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / postsynapse / response to lipopolysaccharide / amyloid fibril formation / molecular adaptor activity / lysosome / transcription cis-regulatory region binding / oxidoreductase activity / positive regulation of apoptotic process
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsLovestam, S.K.A. / Schweighauser, M. / Scheres, S.H.W.
Funding support United Kingdom, Japan, 4items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC-U105184291 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Japan Agency for Medical Research and Development (AMED)JP18ek0109391 Japan
Japan Agency for Medical Research and Development (AMED)JP18dm020719 Japan
CitationJournal: FEBS Open Bio / Year: 2021
Title: Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy.
Authors: Sofia Lövestam / Manuel Schweighauser / Tomoyasu Matsubara / Shigeo Murayama / Taisuke Tomita / Takashi Ando / Kazuko Hasegawa / Mari Yoshida / Airi Tarutani / Masato Hasegawa / Michel ...Authors: Sofia Lövestam / Manuel Schweighauser / Tomoyasu Matsubara / Shigeo Murayama / Taisuke Tomita / Takashi Ando / Kazuko Hasegawa / Mari Yoshida / Airi Tarutani / Masato Hasegawa / Michel Goedert / Sjors H W Scheres /
Abstract: The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of α-synuclein into filaments is believed to underlie the prion-like spreading of ...The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of α-synuclein into filaments is believed to underlie the prion-like spreading of protein inclusions in a number of human neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We previously determined the atomic structures of α-synuclein filaments from the putamen of five individuals with MSA. Here, we used filament preparations from three of these brains for the in vitro seeded assembly of recombinant human α-synuclein. We find that the structures of the seeded assemblies differ from those of the seeds, suggesting that additional, as yet unknown, factors play a role in the propagation of the seeds. Identification of these factors will be essential for understanding the prion-like spreading of α-synuclein proteinopathies.
History
DepositionJan 28, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 24, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2May 1, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

Deposited unit
A: Alpha-synuclein
B: Alpha-synuclein
C: Alpha-synuclein
D: Alpha-synuclein
E: Alpha-synuclein
F: Alpha-synuclein
G: Alpha-synuclein
H: Alpha-synuclein
I: Alpha-synuclein
J: Alpha-synuclein
K: Alpha-synuclein
L: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)173,71312
Polymers173,71312
Non-polymers00
Water00
1
A: Alpha-synuclein
E: Alpha-synuclein
F: Alpha-synuclein
J: Alpha-synuclein
K: Alpha-synuclein
L: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)86,8576
Polymers86,8576
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_5551
2
B: Alpha-synuclein
C: Alpha-synuclein
D: Alpha-synuclein
G: Alpha-synuclein
H: Alpha-synuclein
I: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)86,8576
Polymers86,8576
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Alpha-synuclein / Non-A beta component of AD amyloid / Non-A4 component of amyloid precursor / NACP


Mass: 14476.108 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Plasmid: pRK172-WT-Asyn / Production host: Escherichia coli (E. coli) / References: UniProt: P37840

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Alpha synuclein filament / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli) / Plasmid: pRK172-WT-aSyn
Buffer solutionpH: 6.5
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: LMB vitrobot IV

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 32.6 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategoryDetails
2EPUimage acquisition
4CTFFINDCTF correction
5RELIONCTF correction
14RELION3.13D reconstructionThe purple version :)
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.04 ° / Axial rise/subunit: 4.76 Å / Axial symmetry: C2
3D reconstructionResolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 67619 / Algorithm: FOURIER SPACE / Symmetry type: HELICAL

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