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- PDB-6ssx: cryo-em structure of alpha-synuclein fibril polymorph 2A -

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Basic information

Entry
Database: PDB / ID: 6ssx
Titlecryo-em structure of alpha-synuclein fibril polymorph 2A
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / amyloid / parkinson
Function / homology
Function and homology information


regulation of phospholipase activity / : / 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 ...regulation of phospholipase activity / : / 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 / negative regulation of transporter activity / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of synaptic vesicle recycling / 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 / regulation of locomotion / synaptic vesicle priming / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of endocytosis / synaptic vesicle exocytosis / positive regulation of exocytosis / response to magnesium ion / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / kinesin binding / synaptic vesicle endocytosis / regulation of presynapse assembly / response to type II interferon / negative regulation of serotonin uptake / alpha-tubulin binding / inclusion body / supramolecular fiber organization / phospholipid metabolic process / cellular response to copper ion / cellular response to epinephrine stimulus / axon terminus / Hsp70 protein binding / response to interleukin-1 / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / excitatory postsynaptic potential / fatty acid metabolic process / positive regulation of protein serine/threonine kinase activity / phosphoprotein binding / negative regulation of protein kinase activity / protein tetramerization / long-term synaptic potentiation / regulation of transmembrane transporter activity / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / positive regulation of peptidyl-serine phosphorylation / protein destabilization / PKR-mediated signaling / tau protein binding / receptor internalization / phospholipid binding / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / chemical synaptic transmission / neuron apoptotic process / molecular adaptor activity / response to lipopolysaccharide / negative regulation of neuron apoptotic process / histone binding / amyloid fibril formation / lysosome / oxidoreductase activity / transcription cis-regulatory region binding / postsynapse / positive regulation of apoptotic process / copper ion binding / response to xenobiotic stimulus
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsGuerrero-Ferreira, R. / Taylor, N.M.I. / Arteni, A.A. / Melki, R. / Meier, B.H. / Bockmann, A. / Bousset, L. / Stahlberg, H.
Funding support Switzerland, France, Denmark, French Guiana, 13items
OrganizationGrant numberCountry
Swiss National Science FoundationCRSII3_154461 Switzerland
European Union116060 France
Novo Nordisk FoundationNNF14CC0001 Denmark
Swiss National Science FoundationCRSII3_154461 Switzerland
Swiss National Science FoundationCRSII5_177195 Switzerland
Swiss National Science Foundation20020_178792 Switzerland
French National Research AgencyANR-12- BS08-0013-01 France
French National Research AgencyANR-11-LABX-0048 France
French National Research AgencyANR-11-IDEX-0007 France
Swiss National Science Foundation17.00038 Switzerland
French National Research AgencyANR-17-JPCD-0002-02French Guiana
French National Research AgencyANR-17-JPCD-0005-01French Guiana
French National Research AgencyANR-10-INSB-05-01 France
CitationJournal: Elife / Year: 2019
Title: Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy.
Authors: Ricardo Guerrero-Ferreira / Nicholas Mi Taylor / Ana-Andreea Arteni / Pratibha Kumari / Daniel Mona / Philippe Ringler / Markus Britschgi / Matthias E Lauer / Ali Makky / Joeri Verasdonck / ...Authors: Ricardo Guerrero-Ferreira / Nicholas Mi Taylor / Ana-Andreea Arteni / Pratibha Kumari / Daniel Mona / Philippe Ringler / Markus Britschgi / Matthias E Lauer / Ali Makky / Joeri Verasdonck / Roland Riek / Ronald Melki / Beat H Meier / Anja Böckmann / Luc Bousset / Henning Stahlberg /
Abstract: Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein ...Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.
History
DepositionSep 9, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 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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Structure visualization

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Structure viewerMolecule:
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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


Theoretical massNumber of molelcules
Total (without water)144,76110
Polymers144,76110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area43740 Å2
ΔGint-133 kcal/mol
Surface area26200 Å2
MethodPISA

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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.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli BL21(DE3) (bacteria) / 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 fibril, polymorph 2A / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 51 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTrisHCl1
2150 mMKCl1
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: WT alpha synuclein
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 293 K
Details: 3 uL aliquots were applied onto second glow-discharged 300 mesh copper Quantifoil grids R2 1

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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
Image recordingElectron dose: 69 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
Image scansMovie frames/image: 50

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Processing

EM software
IDNameVersionCategory
1RELION2.1particle selection
2SerialEMimage acquisition
3FOCUSimage acquisition
5MotionCorr2CTF correction
8Cootmodel fitting
10PHENIXmodel refinement
11RELION2.1initial Euler assignment
12RELION2.1final Euler assignment
13RELION2.1classification
14Coot3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 0.8 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C2
3D reconstructionResolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 100323 / Symmetry type: HELICAL
Atomic model buildingProtocol: AB INITIO MODEL

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