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- EMDB-3028: MicroED structure of the toxic core segment, GAVVTGVTAVA, from Pa... -

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Entry
Database: EMDB / ID: EMD-3028
TitleMicroED structure of the toxic core segment, GAVVTGVTAVA, from Parkinson's disease protein, alpha-synuclein, residues 69-78.
Map datamicroED map of toxic NACore segment, residues 68-78 of alpha-synuclein
Sample
  • Sample: GAVVTGVTAVA, a toxic segment from the NAC domain of Parkinson's disease protein, alpha-synuclein, residues 69-78
  • Protein or peptide: alpha synuclein residues 69-78
KeywordsAmyloid fibrils / alpha-synuclein / MicroED Crystallography / Parkinson's Disease / Peptide / Toxicity
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 / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / regulation of norepinephrine uptake / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of macrophage activation / mitochondrial ATP synthesis coupled electron transport / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / dopamine uptake involved in synaptic transmission / positive regulation of receptor recycling / regulation of dopamine secretion / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of endocytosis / synaptic vesicle exocytosis / kinesin binding / positive regulation of exocytosis / response to magnesium ion / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / regulation of presynapse assembly / response to type II interferon / negative regulation of serotonin uptake / synaptic vesicle endocytosis / alpha-tubulin binding / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / cellular response to epinephrine stimulus / phospholipid metabolic process / Hsp70 protein binding / response to interleukin-1 / : / SNARE binding / adult locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / excitatory postsynaptic potential / positive regulation of protein serine/threonine kinase activity / fatty acid metabolic process / phosphoprotein binding / protein tetramerization / negative regulation of protein kinase activity / long-term synaptic potentiation / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / regulation of transmembrane transporter activity / tau protein binding / : / ferrous iron binding / PKR-mediated signaling / protein destabilization / receptor internalization / phospholipid binding / positive regulation of peptidyl-serine phosphorylation / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / cellular response to oxidative stress / histone binding / growth cone / cell cortex / chemical synaptic transmission / neuron apoptotic process / molecular adaptor activity / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / oxidoreductase activity / lysosome / postsynapse / transcription cis-regulatory region binding / positive regulation of apoptotic process
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodelectron crystallography / cryo EM / Resolution: 1.4 Å
AuthorsRodriguez JA / Ivanova M / Sawaya MR / Cascio D / Reyes F / Shi D / Johnson L / Guenther E / Zhang M / Jiang L ...Rodriguez JA / Ivanova M / Sawaya MR / Cascio D / Reyes F / Shi D / Johnson L / Guenther E / Zhang M / Jiang L / Arbing MA / Sangwan S / Hattne J / Whitelegge J / Brewster A / Messerschmidt M / Boutet S / Sauter NK / Nannenga B / Gonen T / Eisenberg D
CitationJournal: Nature / Year: 2015
Title: Structure of the toxic core of α-synuclein from invisible crystals.
Authors: Jose A Rodriguez / Magdalena I Ivanova / Michael R Sawaya / Duilio Cascio / Francis E Reyes / Dan Shi / Smriti Sangwan / Elizabeth L Guenther / Lisa M Johnson / Meng Zhang / Lin Jiang / Mark ...Authors: Jose A Rodriguez / Magdalena I Ivanova / Michael R Sawaya / Duilio Cascio / Francis E Reyes / Dan Shi / Smriti Sangwan / Elizabeth L Guenther / Lisa M Johnson / Meng Zhang / Lin Jiang / Mark A Arbing / Brent L Nannenga / Johan Hattne / Julian Whitelegge / Aaron S Brewster / Marc Messerschmidt / Sébastien Boutet / Nicholas K Sauter / Tamir Gonen / David S Eisenberg /
Abstract: The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term ...The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 Å resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face β-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.
History
DepositionMay 28, 2015-
Header (metadata) releaseJun 10, 2015-
Map releaseSep 9, 2015-
UpdateOct 7, 2015-
Current statusOct 7, 2015Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
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  • Surface view with fitted model
  • Atomic models: PDB-4ril
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-4ril
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Structure viewerEM map:
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Supplemental images

emd_3028.500...

Downloads & links

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Map

FileDownload / File: emd_3028.map.gz / Format: CCP4 / Size: 464.8 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationmicroED map of toxic NACore segment, residues 68-78 of alpha-synuclein
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesY (Sec.)X (Row.)Z (Col.)
0.4 Å/pix.
x 13 pix.
= 4.82 Å		0.46 Å/pix.
x 161 pix.
= 70.81 Å		0.44 Å/pix.
x 58 pix.
= 16.79 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX: 0.45981 Å / Y: 0.40167 Å / Z: 0.44184 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0 / Movie #1: 1
Minimum - Maximum-1.0566808 - 2.5717845
Average (Standard dev.)0.00511681 (±0.48366362)
SymmetrySpace group: 5
Details

EMDB XML:

Map geometry
Axis orderZXY
Origin-80-40
Dimensions1615813
Spacing1215438
CellA: 70.81 Å / B: 4.82 Å / C: 16.79 Å
α: 90.0 ° / β: 105.68 ° / γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.459805194805190.401666666666670.44184210526316
M x/y/z1541238
origin x/y/z0.0000.0000.000
length x/y/z70.8104.82016.790
α/β/γ90.000105.68090.000
start NX/NY/NZ-800-4
NX/NY/NZ1611358
MAP C/R/S312
start NC/NR/NS-4-800
NC/NR/NS5816113
D min/max/mean-1.0572.5720.005

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Supplemental data

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Sample components

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Entire : GAVVTGVTAVA, a toxic segment from the NAC domain of Parkinson's d...

EntireName: GAVVTGVTAVA, a toxic segment from the NAC domain of Parkinson's disease protein, alpha-synuclein, residues 69-78
Components
  • Sample: GAVVTGVTAVA, a toxic segment from the NAC domain of Parkinson's disease protein, alpha-synuclein, residues 69-78
  • Protein or peptide: alpha synuclein residues 69-78

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Supramolecule #1000: GAVVTGVTAVA, a toxic segment from the NAC domain of Parkinson's d...

SupramoleculeName: GAVVTGVTAVA, a toxic segment from the NAC domain of Parkinson's disease protein, alpha-synuclein, residues 69-78
type: sample / ID: 1000 / Details: crystalline fibrils / Oligomeric state: crystalline fibrils / Number unique components: 1
Molecular weightTheoretical: 1 KDa

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Macromolecule #1: alpha synuclein residues 69-78

MacromoleculeName: alpha synuclein residues 69-78 / type: protein_or_peptide / ID: 1 / Name.synonym: a-syn
Details: alpha synuclein residues 68-78. Synthesized chemically.
Number of copies: 1 / Oligomeric state: fibril / Recombinant expression: No / Database: NCBI
Source (natural)Organism: Homo sapiens (human) / synonym: Human
Molecular weightExperimental: 1 KDa

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Experimental details

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Structure determination

Methodcryo EM
Processingelectron crystallography
Aggregation state3D array

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Sample preparation

Concentration1 mg/mL
BufferpH: 7 / Details: water
GridDetails: quantifoil holey-carbon EM grid, 300 mesh copper
VitrificationCryogen name: ETHANE / Chamber temperature: 100 K / Instrument: FEI VITROBOT MARK IV
Method: Nanocrystals were deposited onto a quantifoil holey-carbon EM grid in a 2-3 microliter drop after appropriate dilution, which was optimized for crystal density on the grid. All grids were ...Method: Nanocrystals were deposited onto a quantifoil holey-carbon EM grid in a 2-3 microliter drop after appropriate dilution, which was optimized for crystal density on the grid. All grids were then blotted and vitrified by plunging into liquid ethane using a Vitrobot Mark IV (FEI), then transferring to liquid nitrogen for storage.
DetailsCrystals grew in batch. In a microcentrifuge tube at 37 degrees C with shaking.
Crystal formationDetails: Crystals grew in batch. In a microcentrifuge tube at 37 degrees C with shaking.

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Electron microscopy

MicroscopeFEI TECNAI F20
TemperatureMin: 99 K / Max: 101 K / Average: 100 K
Detailsvery low dose data collection. Spot size 11.
DateAug 28, 2014
Image recordingCategory: CCD / Film or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Average electron dose: 0.10000000000000001 e/Å2 / Camera length: 2230 / Details: Diffraction images are available upon request. / Bits/pixel: 16
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: DIFFRACTION
Sample stageSpecimen holder: liquid nitrogen cooled / Specimen holder model: GATAN LIQUID NITROGEN / Tilt angle min: -66 / Tilt angle max: 66 / Tilt series - Axis1 - Min angle: -66 ° / Tilt series - Axis1 - Max angle: 66 °
Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company

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Image processing

DetailsDiffraction images were processed with XDS and XSCALE.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 1.4 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES
Details: The diffraction data set contains intensities measured from four crystals.
Crystal parametersUnit cell - A: 70.81 Å / Unit cell - B: 4.82 Å / Unit cell - C: 16.79 Å / Unit cell - γ: 90.0 ° / Unit cell - α: 90 ° / Unit cell - β: 105.68 ° / Space group: C 1 2 1

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