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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 / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / regulation of synaptic vesicle recycling / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / regulation of norepinephrine uptake / dopamine biosynthetic process / SNARE complex assembly / positive regulation of neurotransmitter secretion / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / regulation of macrophage activation / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / positive regulation of endocytosis / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / positive regulation of exocytosis / synaptic vesicle exocytosis / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / kinesin binding / alpha-tubulin binding / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / localization / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / Hsp70 protein binding / cellular response to epinephrine stimulus / excitatory postsynaptic potential / response to interleukin-1 / adult locomotory behavior / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / fatty acid metabolic process / long-term synaptic potentiation / regulation of transmembrane transporter activity / ferrous iron binding / synapse organization / phospholipid binding / protein tetramerization / phosphoprotein binding / microglial cell activation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / tau protein binding / protein destabilization / PKR-mediated signaling / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of protein serine/threonine kinase activity / receptor internalization / synaptic vesicle membrane / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / cellular response to oxidative stress / actin binding / cell cortex / growth cone / histone binding / chemical synaptic transmission / postsynapse / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / lysosome / oxidoreductase activity / molecular adaptor activity / transcription cis-regulatory region binding
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

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  • Surface view with section colored by density value
  • Surface level: 1
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  • Surface level: 1
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  • Surface view with fitted model
  • Atomic models: PDB-4ril
  • Surface level: 1
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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
Voxel sizeX: 0.45981 Å / Y: 0.40167 Å / Z: 0.44184 Å
Density
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
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 °
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
Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company

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Image processing

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
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.
DetailsDiffraction images were processed with XDS and XSCALE.

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