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

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Basic information

Entry
Database: PDB / ID: 6flt
TitleStructure of alpha-synuclein fibrils
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / Parkinson's disease / apha-synuclein / fibril / filament
Function / homologySynuclein / Alpha-synuclein / Amyloid fiber formation / Synuclein / negative regulation of monooxygenase activity / positive regulation of glutathione peroxidase activity / regulation of phospholipase activity / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission ...Synuclein / Alpha-synuclein / Amyloid fiber formation / Synuclein / negative regulation of monooxygenase activity / positive regulation of glutathione peroxidase activity / regulation of phospholipase 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 / response to desipramine / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of hydrogen peroxide catabolic process / mitochondrial membrane organization / supramolecular fiber / regulation of glutamate secretion / regulation of reactive oxygen species biosynthetic process / negative regulation of transporter activity / regulation of presynapse assembly / negative regulation of chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of locomotion / positive regulation of neurotransmitter secretion / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of inositol phosphate biosynthetic process / negative regulation of exocytosis / response to iron(II) ion / negative regulation of serotonin uptake / dopamine biosynthetic process / mitochondrial ATP synthesis coupled electron transport / negative regulation of histone acetylation / synaptic vesicle transport / positive regulation of receptor recycling / nuclear outer membrane / dopamine uptake involved in synaptic transmission / negative regulation of microtubule polymerization / regulation of dopamine secretion / synaptic vesicle endocytosis / regulation of macrophage activation / negative regulation of dopamine metabolic process / supramolecular fiber organization / kinesin binding / dynein complex binding / beta-tubulin binding / alpha-tubulin binding / response to magnesium ion / positive regulation of endocytosis / response to interferon-gamma / cuprous ion binding / cellular response to fibroblast growth factor stimulus / cellular response to copper ion / negative regulation of thrombin-activated receptor signaling pathway / excitatory postsynaptic potential / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / microglial cell activation / response to interleukin-1 / behavioral response to cocaine / long-term synaptic potentiation / fatty acid metabolic process / inclusion body / Hsp70 protein binding / synapse organization / adult locomotory behavior / phospholipid metabolic process / synaptic vesicle / tau protein binding / cellular response to epinephrine stimulus / postsynapse / ferrous iron binding / positive regulation of protein serine/threonine kinase activity / rough endoplasmic reticulum / negative regulation of protein phosphorylation / regulation of long-term neuronal synaptic plasticity / receptor internalization / negative regulation of neuron death / terminal bouton / positive regulation of release of sequestered calcium ion into cytosol / protein destabilization / phospholipid binding / cytoplasmic vesicle membrane / positive regulation of inflammatory response / phosphoprotein binding / mitochondrial intermembrane space / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / growth cone / positive regulation of neuron death / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / cell cortex / cellular response to oxidative stress / mitochondrial inner membrane / histone binding / protein N-terminus binding / transcription regulatory region DNA binding / ribosome / lysosome / positive regulation of peptidyl-serine phosphorylation / mitochondrial outer membrane / negative regulation of neuron apoptotic process
Function and homology information
Specimen sourceHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / 3.42 Å resolution
AuthorsGuerrero-Ferreira, R. / Taylor, N.M.I. / Mona, D. / Riek, R. / Britschgi, M. / Stahlberg, H.
CitationJournal: Elife / Year: 2018
Title: Cryo-EM structure of alpha-synuclein fibrils.
Authors: Ricardo Guerrero-Ferreira / Nicholas M I 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 synucleopathies, 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 synucleopathies, 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 structure at a resolution of 3.4Å. 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: Jan 28, 2018 / Release: Jun 27, 2018
RevisionDateData content typeGroupCategoryItemProviderType
1.0Jun 27, 2018Structure modelrepositoryInitial release
1.1Jul 11, 2018Structure modelData collection / Database referencescitation / citation_author_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

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Structure visualization

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  • Deposited structure unit
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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)122,42910
Polyers122,42910
Non-polymers00
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)37460
ΔGint (kcal/M)-133
Surface area (Å2)21870
MethodPISA

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Components

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


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: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 13390 / Symmetry type: POINT

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