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- PDB-8oqi: Cryo-EM structure of the wild-type alpha-synuclein fibril. -

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Basic information

Entry
Database: PDB / ID: 8oqi
TitleCryo-EM structure of the wild-type alpha-synuclein fibril.
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / alpha-synuclein / amyloid / fibril / Parkinson's disease
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / 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 / mitochondrial membrane organization ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / 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 / 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 / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of norepinephrine uptake / transporter regulator activity / regulation of locomotion / synaptic vesicle priming / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle transport / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / dynein complex binding / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of endocytosis / positive regulation of exocytosis / response to magnesium ion / synaptic vesicle exocytosis / enzyme inhibitor activity / kinesin binding / synaptic vesicle endocytosis / regulation of presynapse assembly / response to type II interferon / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / alpha-tubulin binding / supramolecular fiber organization / inclusion body / phospholipid metabolic process / cellular response to copper ion / axon terminus / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / negative regulation of protein kinase activity / excitatory postsynaptic potential / fatty acid metabolic process / phosphoprotein binding / protein tetramerization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / protein destabilization / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / neuron apoptotic process / chemical synaptic transmission / molecular adaptor activity / negative regulation of neuron apoptotic process / response to lipopolysaccharide / histone binding / amyloid fibril formation / lysosome / oxidoreductase activity / postsynapse / transcription cis-regulatory region binding / positive regulation of apoptotic process / Amyloid fiber formation / copper ion binding / response to xenobiotic stimulus / axon / neuronal cell body
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsPesch, V. / Reithofer, S. / Ma, L. / Flores-Fernandez, J.M. / Oezduezenciler, P. / Busch, Y. / Lien, Y. / Rudtke, O. / Frieg, B. / Schroeder, G.F. ...Pesch, V. / Reithofer, S. / Ma, L. / Flores-Fernandez, J.M. / Oezduezenciler, P. / Busch, Y. / Lien, Y. / Rudtke, O. / Frieg, B. / Schroeder, G.F. / Wille, H. / Tamgueney, G.
Funding support United States, Germany, 2items
OrganizationGrant numberCountry
Michael J. Fox FoundationMJFF-0098 United States
Helmholtz Association Germany
CitationJournal: Brain / Year: 2024
Title: Vaccination with structurally adapted fungal protein fibrils induces immunity to Parkinson's disease.
Authors: Verena Pesch / José Miguel Flores-Fernandez / Sara Reithofer / Liang Ma / Pelin Özdüzenciler / Yannick Busch / Aishwarya Sriraman / YongLiang Wang / Sara Amidian / Chiara V M Kroepel / ...Authors: Verena Pesch / José Miguel Flores-Fernandez / Sara Reithofer / Liang Ma / Pelin Özdüzenciler / Yannick Busch / Aishwarya Sriraman / YongLiang Wang / Sara Amidian / Chiara V M Kroepel / Laura Müller / Yi Lien / Olivia Rudtke / Benedikt Frieg / Gunnar F Schröder / Holger Wille / Gültekin Tamgüney /
Abstract: The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, a progressive age-related neurodegenerative disease ...The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, a progressive age-related neurodegenerative disease for which there is no cure. HET-s is a soluble fungal protein that can form assembled amyloid fibrils in its prion state. We engineered HET-s(218-298) to form four different fibrillar vaccine candidates, each displaying a specific conformational epitope present on the surface of α-synuclein fibrils. Vaccination with these four vaccine candidates prolonged the survival of immunized TgM83+/- mice challenged with α-synuclein fibrils by 8% when injected into the brain to model brain-first Parkinson's disease or by 21% and 22% when injected into the peritoneum or gut wall, respectively, to model body-first Parkinson's disease. Antibodies from fully immunized mice recognized α-synuclein fibrils and brain homogenates from patients with Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Conformation-specific vaccines that mimic epitopes present only on the surface of pathological fibrils but not on soluble monomers, hold great promise for protection against Parkinson's disease, related synucleinopathies and other amyloidogenic protein misfolding disorders.
History
DepositionApr 12, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)144,76110
Polymers144,76110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "D"
d_5ens_1chain "E"
d_6ens_1chain "F"
d_7ens_1chain "G"
d_8ens_1chain "H"
d_9ens_1chain "I"
d_10ens_1chain "J"

NCS domain segments:

Component-ID: 1 / Ens-ID: ens_1 / Beg auth comp-ID: TYR / Beg label comp-ID: TYR / End auth comp-ID: PHE / End label comp-ID: PHE / Auth seq-ID: 39 - 94 / Label seq-ID: 39 - 94

Dom-IDAuth asym-IDLabel asym-ID
d_1AA
d_2BB
d_3CC
d_4DD
d_5EE
d_6FF
d_7GG
d_8HH
d_9II
d_10JJ

NCS oper:
IDCodeMatrixVector
1given(-0.999977677497, -0.00668165454656, -5.62849764392E-7), (0.00668165454668, -0.999977677497, -2.13326670996E-7), (-5.61411825055E-7, -2.17082676698E-7, 1)265.882471825, 264.11171345, 2.41009282691
2given(0.999910690911, 0.0133645127859, 6.4676325693E-7), (-0.0133645127861, 0.999910690911, 3.09458445897E-7), (-6.42569733736E-7, -3.18074484262E-7, 1)-1.75903992619, 1.78261234224, 4.82011482535
3given(-0.999799090767, -0.0200444032475, -3.05348574424E-7), (0.0200444032476, -0.999799090767, -1.53338411269E-7), (-3.02213650127E-7, -1.59428134123E-7, 1)267.629328902, 262.317484291, 7.23005521638
4given(0.999642848698, 0.0267240537246, 2.61142270104E-7), (-0.0267240537246, 0.999642848698, -5.41057996486E-9), (-2.61193595431E-7, -1.57013248684E-9, 1)-3.4937054614, 3.58827903434, 9.64003093305
5given(-0.999441932354, -0.0334039496667, -3.56636455179E-7), (0.0334039496668, -0.999441932354, -1.68178096599E-7), (-3.50819615238E-7, -1.79997308043E-7, 1)269.352140043, 260.500047529, 12.0500634719
6given(0.999196421546, 0.0400813069954, 2.31604063537E-7), (-0.0400813069954, 0.999196421546, 1.68238442329E-8), (-2.30743629836E-7, -2.60933185262E-8, 1)-5.20434510708, 5.41722148086, 14.4600303719
7given(-0.998906319755, -0.0467564365014, -2.79586581782E-8), (0.0467564365014, -0.998906319755, 1.14224783105E-7), (-3.32688241642E-8, 1.12792610491E-7, 1)271.050327488, 258.659811318, 16.8699900139
8given(0.998571501207, 0.0534317974369, 5.28131209778E-7), (-0.0534317974371, 0.998571501207, 3.76369752301E-7), (-5.07266662616E-7, -4.04051108385E-7, 1)-6.89049041568, 7.26890954537, 19.2801094982
9given(-0.998192226534, -0.0601022369574, -6.12794325452E-7), (0.0601022369577, -0.998192226534, -4.46010244537E-7), (-5.84880318727E-7, -4.82034268806E-7, 1)272.724098091, 256.796967462, 21.6901282437

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Components

#1: Protein
Alpha-synuclein / Non-A beta component of AD amyloid / Non-A4 component of amyloid precursor / NACP


Mass: 14476.108 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Details: N-terminally acetylated human wild-type alpha-synuclein.
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P37840

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Human wild-type alpha-synuclein fibril / Type: COMPLEX
Details: N-terminally acetylated human wild-type alpha-synuclein
Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 179.62 ° / Axial rise/subunit: 2.41 Å / Axial symmetry: C1
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 27610
Details: The alpha-synuclein fibril was reconstructed using RELION-3.1.
Symmetry type: HELICAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 56.31 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01313830
ELECTRON MICROSCOPYf_angle_d2.0085190
ELECTRON MICROSCOPYf_chiral_restr0.1147680
ELECTRON MICROSCOPYf_plane_restr0.0068650
ELECTRON MICROSCOPYf_dihedral_angle_d18.28631260
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AELECTRON MICROSCOPYNCS constraints0.000582599456592
ens_1d_3AELECTRON MICROSCOPYNCS constraints0.000563242468017
ens_1d_4AELECTRON MICROSCOPYNCS constraints0.000579861558612
ens_1d_5AELECTRON MICROSCOPYNCS constraints0.000564553631986
ens_1d_6AELECTRON MICROSCOPYNCS constraints0.000408143770637
ens_1d_7AELECTRON MICROSCOPYNCS constraints0.000573924979394
ens_1d_8AELECTRON MICROSCOPYNCS constraints0.000578506874847
ens_1d_9AELECTRON MICROSCOPYNCS constraints0.00056769526007
ens_1d_10AELECTRON MICROSCOPYNCS constraints0.000594551183008

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