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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 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 / positive regulation of inositol phosphate biosynthetic process / mitochondrial ATP synthesis coupled electron transport / 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 / histone binding / growth cone / chemical synaptic transmission / postsynapse / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / lysosome / molecular adaptor activity / oxidoreductase activity / transcription cis-regulatory region binding
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 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

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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
Water0
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 FIELDBright-field microscopy / 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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