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- PDB-6h6b: Structure of alpha-synuclein fibrils -

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Basic information

Entry
Database: PDB / ID: 6h6b
TitleStructure of alpha-synuclein fibrils
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / Parkinson's disease / apha-synuclein / fibril / filament
Function / homology
Function and homology information


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 / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / 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 / response to iron(II) ion / regulation of norepinephrine uptake / dopamine biosynthetic process / SNARE complex assembly / positive regulation of neurotransmitter secretion / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / regulation of macrophage activation / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / mitochondrial ATP synthesis coupled electron transport / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / positive regulation of endocytosis / 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 / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / kinesin binding / alpha-tubulin binding / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / 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 / regulation of transmembrane transporter activity / ferrous iron binding / synapse organization / phospholipid binding / protein tetramerization / phosphoprotein binding / microglial cell activation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / tau protein binding / protein destabilization / PKR-mediated signaling / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of protein serine/threonine kinase activity / receptor internalization / 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 / cellular response to oxidative stress / actin binding / cell cortex / histone binding / growth cone / chemical synaptic transmission / postsynapse / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / lysosome / molecular adaptor activity / oxidoreductase activity / transcription cis-regulatory region binding
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsGuerrero-Ferreira, R. / Taylor, N.M.I. / Mona, D. / Ringler, P. / Lauer, M.E. / Riek, R. / Britschgi, M. / Stahlberg, H.
Funding support Switzerland, 2items
OrganizationGrant numberCountry
Switzerland
Switzerland
CitationJournal: Elife / Year: 2018
Title: Cryo-EM structure of alpha-synuclein fibrils.
Authors: Ricardo Guerrero-Ferreira / Nicholas Mi Taylor / Daniel Mona / Philippe Ringler / Matthias E Lauer / Roland Riek / Markus Britschgi / Henning Stahlberg /
Abstract: Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in ...Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.
History
DepositionJul 26, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
SupersessionSep 5, 2018ID: 6FLT
Revision 1.1Sep 5, 2018Group: Advisory / Data collection / Database references
Category: citation / citation_author / pdbx_database_PDB_obs_spr
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Dec 18, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]
Revision 1.3Feb 22, 2023Group: Advisory / Database references / Category: database_2 / pdbx_database_PDB_obs_spr
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_PDB_obs_spr.replace_pdb_id

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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)122,42910
Polymers122,42910
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area37160 Å2
ΔGint-140 kcal/mol
Surface area21490 Å2
MethodPISA

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Components

#1: Protein
Alpha-synuclein /


Mass: 12242.873 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Plasmid: pET21
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (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 fibrils / Type: COMPLEX / Details: Residues 1-121 / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Plasmid: pET21
Buffer solutionpH: 7.3
Buffer component
IDConc.NameFormulaBuffer-ID
12.66 mMPotassium chlorideKCl1
21.47 mMPotassium phosphateKH2PO41
3137.93 mMSodium chlorideNaClSodium chloride1
48.06 mMSodium phosphateNa2HPO41
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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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 FIELDBright-field microscopy
Image recordingElectron dose: 100 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS
Image scansMovie frames/image: 50 / Used frames/image: 2-50

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameCategory
1RELIONparticle selection
2SerialEMimage acquisition
4CTFFINDCTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.5 ° / Axial rise/subunit: 2.45 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 18860
Details: Segments extracted from 792 manually picked fibrils
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 13390 / Symmetry type: HELICAL

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