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- EMDB-0148: Structure of alpha-synuclein fibrils -

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Basic information

Entry
Database: EMDB / ID: 0148
TitleStructure of alpha-synuclein fibrils
Map dataStructure of alpha-synuclein fibrils
SampleAlpha-synuclein fibrils:
Alpha-synuclein
Function / homologyAmyloid fiber formation / Synuclein / Alpha-synuclein / 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 ...Amyloid fiber formation / Synuclein / Alpha-synuclein / 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 / response to desipramine / negative regulation of norepinephrine uptake / 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 / negative regulation of chaperone-mediated autophagy / regulation of presynapse assembly / regulation of norepinephrine uptake / 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 / negative regulation of microtubule polymerization / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / nuclear outer membrane / synaptic vesicle endocytosis / regulation of macrophage activation / negative regulation of dopamine metabolic process / dynein complex binding / beta-tubulin binding / supramolecular fiber organization / alpha-tubulin binding / phospholipase binding / kinesin binding / positive regulation of endocytosis / response to magnesium ion / cuprous ion binding / cellular response to fibroblast growth factor stimulus / cellular response to copper ion / response to interferon-gamma / negative regulation of thrombin-activated receptor signaling pathway / excitatory postsynaptic potential / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to interleukin-1 / behavioral response to cocaine / microglial cell activation / inclusion body / long-term synaptic potentiation / fatty acid metabolic process / regulation of transmembrane transporter activity / Hsp70 protein binding / synapse organization / adult locomotory behavior / phospholipid metabolic process / cellular response to epinephrine stimulus / tau protein binding / postsynapse / synaptic vesicle / 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 / positive regulation of release of sequestered calcium ion into cytosol / protein destabilization / terminal bouton / negative regulation of neuron death / phospholipid binding / cytoplasmic vesicle membrane / positive regulation of inflammatory response / phosphoprotein binding / mitochondrial intermembrane space / actin cytoskeleton / activation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / cell cortex / positive regulation of neuron death / growth cone / cellular response to oxidative stress / mitochondrial inner membrane / actin binding / histone binding / transcription regulatory region DNA binding / ribosome / lysosome
Function and homology information
SourceHomo sapiens (human)
Methodhelical reconstruction / cryo EM / 3.4 Å resolution
AuthorsGuerrero-Ferreira R / Taylor NMI / Mona D / Ringler P / Lauer ME / 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 ReportPDB-ID: 6h6b

SummaryFull reportAbout validation report
DateDeposition: Jul 26, 2018 / Header (metadata) release: Mar 14, 2018 / Map release: Aug 8, 2018 / Last update: Aug 8, 2018

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.029
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.029
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6h6b
  • Surface level: 0.029
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic models: PDB-6h6b
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_0148.map.gz (map file in CCP4 format, 87809 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
280 pix
0.83 Å/pix.
= 232.68 Å
280 pix
0.83 Å/pix.
= 232.68 Å
280 pix
0.83 Å/pix.
= 232.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.831 Å
Density
Contour Level:0.029 (by author), 0.029 (movie #1):
Minimum - Maximum-0.08086198 - 0.16965547
Average (Standard dev.)0.0020613861 (0.007307958)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions280280280
Origin0.0.0.
Limit279.279.279.
Spacing280280280
CellA=B=C: 232.68 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8310.8310.831
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z232.680232.680232.680
α/β/γ90.00090.00090.000
start NX/NY/NZ
NX/NY/NZ
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0810.1700.002

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Supplemental data

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Sample components

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Entire Alpha-synuclein fibrils

EntireName: Alpha-synuclein fibrils / Details: Residues 1-121 / Number of components: 2

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Component #1: protein, Alpha-synuclein fibrils

ProteinName: Alpha-synuclein fibrils / Details: Residues 1-121 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Vector: pET21

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Component #2: protein, Alpha-synuclein

ProteinName: Alpha-synuclein / Number of Copies: 10 / Recombinant expression: No
MassTheoretical: 12.242873 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)

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Experimental details

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Sample preparation

SpecimenSpecimen state: filament / Method: cryo EM
Helical parametersAxial symmetry: C1 (asymmetric) / Hand: RIGHT HANDED / Delta z: 2.45 Å / Delta phi: 179.5 deg.
Sample solutionSpecimen conc.: 5 mg/ml / pH: 7.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 277 K / Humidity: 95 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 1 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD / Energy filter: GIF Quantum LS
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: helical reconstruction
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot
(resolution estimation)

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Atomic model buiding

Output model

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