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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 / homologyAlpha-synuclein / Synuclein / Amyloid fiber formation / Synuclein / negative regulation of mitochondrial electron transport, NADH to ubiquinone / negative regulation of norepinephrine uptake / negative regulation of dopamine uptake involved in synaptic transmission / regulation of acyl-CoA biosynthetic process / positive regulation of glutathione peroxidase activity / regulation of phospholipase activity ...Alpha-synuclein / Synuclein / Amyloid fiber formation / Synuclein / negative regulation of mitochondrial electron transport, NADH to ubiquinone / negative regulation of norepinephrine uptake / negative regulation of dopamine uptake involved in synaptic transmission / regulation of acyl-CoA biosynthetic process / positive regulation of glutathione peroxidase activity / regulation of phospholipase activity / neutral lipid metabolic process / response to desipramine / negative regulation of monooxygenase activity / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / negative regulation of chaperone-mediated autophagy / regulation of glutamate secretion / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / negative regulation of transporter activity / regulation of norepinephrine uptake / regulation of synaptic vesicle recycling / regulation of locomotion / 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 / synaptic vesicle transport / negative regulation of histone acetylation / positive regulation of receptor recycling / negative regulation of microtubule polymerization / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / nuclear outer membrane / regulation of macrophage activation / negative regulation of dopamine metabolic process / dynein complex binding / beta-tubulin binding / alpha-tubulin binding / supramolecular fiber organization / phospholipase binding / kinesin binding / response to magnesium ion / positive regulation of endocytosis / synaptic vesicle endocytosis / response to interferon-gamma / negative regulation of thrombin-activated receptor signaling pathway / cellular response to fibroblast growth factor stimulus / cuprous ion binding / regulation of presynapse assembly / excitatory postsynaptic potential / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to interleukin-1 / behavioral response to cocaine / long-term synaptic potentiation / microglial cell activation / inclusion body / regulation of transmembrane transporter activity / synapse organization / adult locomotory behavior / phospholipid metabolic process / cellular response to epinephrine stimulus / Hsp70 protein binding / tau protein binding / fatty acid metabolic process / positive regulation of protein serine/threonine kinase activity / ferrous iron binding / rough endoplasmic reticulum / receptor internalization / regulation of long-term neuronal synaptic plasticity / negative regulation of protein phosphorylation / synaptic vesicle membrane / positive regulation of release of sequestered calcium ion into cytosol / terminal bouton / cellular response to copper ion / protein destabilization / negative regulation of neuron death / phospholipid binding / positive regulation of inflammatory response / phosphoprotein binding / postsynapse / mitochondrial intermembrane space / actin cytoskeleton / activation of cysteine-type endopeptidase activity involved in apoptotic process / cell cortex / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron death / cellular response to oxidative stress / growth cone / histone binding / mitochondrial inner membrane / actin binding / lysosome / transcription regulatory region DNA binding / protein N-terminus binding / positive regulation of peptidyl-serine phosphorylation
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 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: 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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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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