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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 / homologySynuclein / Synuclein / Amyloid fiber formation / Alpha-synuclein / negative regulation of dopamine uptake involved in synaptic transmission / regulation of acyl-CoA biosynthetic process / response to desipramine / regulation of phospholipase activity / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity ...Synuclein / Synuclein / Amyloid fiber formation / Alpha-synuclein / negative regulation of dopamine uptake involved in synaptic transmission / regulation of acyl-CoA biosynthetic process / response to desipramine / regulation of phospholipase activity / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / negative regulation of monooxygenase activity / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / regulation of glutamate secretion / regulation of reactive oxygen species biosynthetic process / negative regulation of transporter activity / negative regulation of chaperone-mediated autophagy / regulation of norepinephrine uptake / regulation of locomotion / regulation of synaptic vesicle recycling / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / positive regulation of inositol phosphate biosynthetic process / response to iron(II) ion / positive regulation of neurotransmitter secretion / negative regulation of serotonin uptake / mitochondrial ATP synthesis coupled electron transport / dopamine biosynthetic process / negative regulation of histone acetylation / synaptic vesicle transport / negative regulation of microtubule polymerization / dopamine uptake involved in synaptic transmission / nuclear outer membrane / positive regulation of receptor recycling / regulation of dopamine secretion / dynein complex binding / regulation of macrophage activation / negative regulation of dopamine metabolic process / beta-tubulin binding / supramolecular fiber organization / alpha-tubulin binding / phospholipase binding / kinesin binding / response to magnesium ion / positive regulation of endocytosis / response to interferon-gamma / negative regulation of thrombin-activated receptor signaling pathway / cellular response to fibroblast growth factor stimulus / synaptic vesicle endocytosis / cuprous ion binding / regulation of presynapse assembly / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / behavioral response to cocaine / excitatory postsynaptic potential / response to interleukin-1 / inclusion body / regulation of transmembrane transporter activity / synapse organization / Hsp70 protein binding / microglial cell activation / adult locomotory behavior / phospholipid metabolic process / cellular response to epinephrine stimulus / long-term synaptic potentiation / tau protein binding / positive regulation of protein serine/threonine kinase activity / fatty acid metabolic process / synaptic vesicle membrane / rough endoplasmic reticulum / negative regulation of protein phosphorylation / ferrous iron binding / receptor internalization / positive regulation of release of sequestered calcium ion into cytosol / regulation of long-term neuronal synaptic plasticity / protein destabilization / cellular response to copper ion / negative regulation of neuron death / phosphoprotein binding / positive regulation of inflammatory response / terminal bouton / phospholipid binding / mitochondrial intermembrane space / postsynapse / actin cytoskeleton / activation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron death / cell cortex / cellular response to oxidative stress / growth cone / actin binding / mitochondrial inner membrane / histone binding / transcription regulatory region DNA binding / protein N-terminus binding / positive regulation of peptidyl-serine phosphorylation / ribosome
Function and homology information
Specimen sourceHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / 3.4 Å resolution
AuthorsGuerrero-Ferreira, R. / Taylor, N.M.I. / Mona, D. / Ringler, P. / Lauer, M.E. / Riek, R. / Britschgi, M. / Stahlberg, H.
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.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Jul 26, 2018 / Release: Aug 8, 2018
RevisionDateData content typeGroupCategoryItemProviderType
1.0Aug 8, 2018Structure modelrepositoryInitial release
1.1Sep 5, 2018Structure modelAdvisory / Data collection / Database referencescitation / citation_author / pdbx_database_PDB_obs_spr_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

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Structure visualization

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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
Polyers122,42910
Non-polymers00
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)37160
ΔGint (kcal/M)-140
Surface area (Å2)21490
MethodPISA

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Components

#1: Protein/peptide
Alpha-synuclein /


Mass: 12242.873 Da / Num. of mol.: 10 / Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Plasmid name: 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 / Reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Alpha-synuclein fibrils / Type: COMPLEX / Details: Residues 1-121 / Entity ID: 1 / 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 chlorideNaCl1
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 / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 kelvins

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyMicroscope model: 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 deg. / Axial rise/subunit: 2.45 Å / Axial symmetry: C1
Particle selectionDetails: Segments extracted from 792 manually picked fibrils
Number of particles selected: 18860
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 13390 / Symmetry type: HELICAL

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