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- EMDB-4996: cryo-em structure of alpha-synuclein fibril polymorph 2B -

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Entry
Database: EMDB / ID: EMD-4996
Titlecryo-em structure of alpha-synuclein fibril polymorph 2B
Map datacryo-em structure of alpha-synuclein fibril, polymorph 2B
Sample
  • Complex: alpha synuclein fibril, polymorph 2B
    • Protein or peptide: Alpha-synuclein
Keywordsamyloid / parkinson / PROTEIN FIBRIL
Function / homology
Function and homology information


regulation of phospholipase activity / negative regulation of monooxygenase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of glutathione peroxidase 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 / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process ...regulation of phospholipase activity / negative regulation of monooxygenase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of glutathione peroxidase 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 / 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 reactive oxygen species biosynthetic process / regulation of synaptic vesicle recycling / 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 / 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 / response to type II interferon / cuprous ion binding / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / mitochondrial ATP synthesis coupled electron transport / synaptic vesicle endocytosis / regulation of presynapse assembly / negative regulation of serotonin uptake / alpha-tubulin binding / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / : / adult locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / excitatory postsynaptic potential / fatty acid metabolic process / long-term synaptic potentiation / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / protein destabilization / negative regulation of protein kinase activity / microglial cell activation / synapse organization / regulation of long-term neuronal synaptic plasticity / ferrous iron binding / positive regulation of protein serine/threonine kinase activity / tau protein binding / PKR-mediated signaling / receptor internalization / : / phospholipid binding / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / actin binding / cell cortex / cellular response to oxidative stress / histone binding / growth cone / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / postsynapse / response to lipopolysaccharide / amyloid fibril formation / molecular adaptor activity / lysosome / transcription cis-regulatory region binding / oxidoreductase activity / positive regulation of apoptotic process
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsGuerrero-Ferreira R / Taylor NMI
Funding support Switzerland, France, 2 items
OrganizationGrant numberCountry
Swiss National Science FoundationCRSII3_154461 Switzerland
European Union116060 France
Citation
Journal: Elife / Year: 2019
Title: Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy.
Authors: Ricardo Guerrero-Ferreira / Nicholas Mi Taylor / Ana-Andreea Arteni / Pratibha Kumari / Daniel Mona / Philippe Ringler / Markus Britschgi / Matthias E Lauer / Ali Makky / Joeri Verasdonck / ...Authors: Ricardo Guerrero-Ferreira / Nicholas Mi Taylor / Ana-Andreea Arteni / Pratibha Kumari / Daniel Mona / Philippe Ringler / Markus Britschgi / Matthias E Lauer / Ali Makky / Joeri Verasdonck / Roland Riek / Ronald Melki / Beat H Meier / Anja Böckmann / Luc Bousset / Henning Stahlberg /
Abstract: Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein ...Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.
#1: Journal: Biorxiv / Year: 2019
Title: Two new polymorphic structures of alpha-synuclein solved by cryo-electron microscopy
Authors: Guerrero-Ferreira R / Taylor NMI / Arteni AA / Melki R / Meier BH / Bockmann A / Bousset L / Stahlberg H
History
DepositionMay 22, 2019-
Header (metadata) releaseJun 26, 2019-
Map releaseJun 26, 2019-
UpdateMay 22, 2024-
Current statusMay 22, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.005
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.005
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6rtb
  • Surface level: 0.005
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_4996.png

Downloads & links

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Map

FileDownload / File: emd_4996.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-em structure of alpha-synuclein fibril, polymorph 2B
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 280 pix.
= 183.568 Å		0.66 Å/pix.
x 280 pix.
= 183.568 Å		0.66 Å/pix.
x 280 pix.
= 183.568 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6556 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005 / Movie #1: 0.005
Minimum - Maximum-0.022769723 - 0.046321973
Average (Standard dev.)0.00014467904 (±0.0014031244)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 183.56801 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.65560.65560.6556
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z183.568183.568183.568
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ304304304
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0230.0460.000

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Supplemental data

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Sample components

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Entire : alpha synuclein fibril, polymorph 2B

EntireName: alpha synuclein fibril, polymorph 2B
Components
  • Complex: alpha synuclein fibril, polymorph 2B
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: alpha synuclein fibril, polymorph 2B

SupramoleculeName: alpha synuclein fibril, polymorph 2B / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

UniProtKB: Alpha-synuclein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration10 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
50.0 mMTrisHCl
150.0 mMKCl
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK II
Details: 3 uL aliquots were applied onto second glow-discharged 300 mesh copper Quantifoil grids R2 1.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 69.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.91 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.73 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: Coot / Number images used: 28079
Segment selectionNumber selected: 100323
Startup modelType of model: OTHER / Details: tube volume
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 2.1)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-6rtb:
cryo-em structure of alpha-synuclein fibril polymorph 2B

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