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- PDB-10xu: Structure of amplified aSyn filament by using seed amplification ... -

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Basic information

Entry
Database: PDB / ID: 10xu
TitleStructure of amplified aSyn filament by using seed amplification assay (SAA) from MSA patient CSF.
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / aSyn filament / Seed amplification assay / amyloid filament / Prion strain / Prion like propagation
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 / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / regulation of synaptic vesicle recycling ...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 / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / mitochondrial membrane organization / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / positive regulation of neurotransmitter secretion / regulation of macrophage activation / negative regulation of dopamine metabolic process / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of thrombin-activated receptor signaling pathway / Lewy body / regulation of locomotion / negative regulation of microtubule polymerization / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of norepinephrine uptake / transporter regulator activity / protein kinase inhibitor activity / synaptic vesicle transport / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / positive regulation of receptor recycling / positive regulation of exocytosis / cuprous ion binding / mitochondrial ATP synthesis coupled electron transport / nuclear outer membrane / dynein complex binding / response to magnesium ion / synaptic vesicle exocytosis / positive regulation of endocytosis / negative regulation of serotonin uptake / response to type II interferon / kinesin binding / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / supramolecular fiber organization / phospholipid metabolic process / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / response to interleukin-1 / axon terminus / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / regulation of microtubule cytoskeleton organization / SNARE binding / adult locomotory behavior / glutathione metabolic process / protein tetramerization / excitatory postsynaptic potential / protein sequestering activity / phosphoprotein binding / tubulin binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / regulation of long-term neuronal synaptic plasticity / synapse organization / receptor internalization / phospholipid binding / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / growth cone / actin binding / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / amyloid fibril formation / chemical synaptic transmission
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsBanerjee, V. / Wang, F. / Baker, M.L. / Serysheva, I.I. / Soto, C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
Michael J. Fox Foundation United States
Citation
Journal: Nat Commun / Year: 2025
Title: Seed amplification of MSA alpha-synuclein aggregates preserves the biological and structural properties of brain-derived aggregates.
Authors: Fei Wang / Victor Banerjee / Carla Barria / Santiago Ramirez / Tyler Allison / Damian Gorski / Haley Evans / Quynh Nguyen / Danielle Harrison / Rabab Al-Lahham / Nicole De Gregorio Carbonell ...Authors: Fei Wang / Victor Banerjee / Carla Barria / Santiago Ramirez / Tyler Allison / Damian Gorski / Haley Evans / Quynh Nguyen / Danielle Harrison / Rabab Al-Lahham / Nicole De Gregorio Carbonell / Michelle Pinho / Sanne Kaalund / Jonas Folke / Susana Aznar / Luis Concha-Marambio / Mohd Ishtikhar / Venkata Kps Mallampalli / Sandra Pritzkow / Mohammad Shahnawaz / Matthew L Baker / Irina Serysheva / Claudio Soto /
Abstract: Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence ...Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence showed that αSyn aggregates exist as distinct conformational strains in different synucleinopathies. Recently, we reported that the αSyn Seed Amplification Assay (αSyn-SAA) can amplify and distinguish αSyn strains from PD and MSA. In this study, we investigate whether MSA-seeded, SAA-amplified αSyn fibrils retain the biological and structural properties of the αSyn seeds present in MSA brains. We study the biological activities of both brain-derived and SAA-amplified αSyn aggregates using an αSyn "biosensor" cell model and a synucleinopathy transmission mouse model. Our in vitro and in vivo findings reveal that the SAA-amplified αSyn fibrils preserve the biological properties of the brain-derived MSA strain. Detailed analyses of the in vivo studies demonstrate that both brain-derived and SAA-generated αSyn aggregates induce a similar disease, with comparable incubation periods, neuropathological damages and clinical manifestations. High-resolution cryo-EM analysis of SAA-amplified αSyn fibrils demonstrates that their conformation at the protofilament level closely resembles one of the αSyn filaments previously identified in MSA patient brains. Our findings suggest that SAA can amplify disease-specific misfolded αSyn conformation while preserving its main biological properties.
#1: Journal: Nat Commun / Year: 2025
Title: Seed amplification of MSA alpha-synuclein aggregates preserves the biological and structural properties of brain-derived aggregates.
Authors: Fei Wang / Victor Banerjee / Carla Barria / Santiago Ramirez / Tyler Allison / Damian Gorski / Haley Evans / Quynh Nguyen / Danielle Harrison / Rabab Al-Lahham / Nicole De Gregorio Carbonell ...Authors: Fei Wang / Victor Banerjee / Carla Barria / Santiago Ramirez / Tyler Allison / Damian Gorski / Haley Evans / Quynh Nguyen / Danielle Harrison / Rabab Al-Lahham / Nicole De Gregorio Carbonell / Michelle Pinho / Sanne Kaalund / Jonas Folke / Susana Aznar / Luis Concha-Marambio / Mohd Ishtikhar / Venkata Kps Mallampalli / Sandra Pritzkow / Mohammad Shahnawaz / Matthew L Baker / Irina Serysheva / Claudio Soto /
Abstract: Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence ...Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence showed that αSyn aggregates exist as distinct conformational strains in different synucleinopathies. Recently, we reported that the αSyn Seed Amplification Assay (αSyn-SAA) can amplify and distinguish αSyn strains from PD and MSA. In this study, we investigate whether MSA-seeded, SAA-amplified αSyn fibrils retain the biological and structural properties of the αSyn seeds present in MSA brains. We study the biological activities of both brain-derived and SAA-amplified αSyn aggregates using an αSyn "biosensor" cell model and a synucleinopathy transmission mouse model. Our in vitro and in vivo findings reveal that the SAA-amplified αSyn fibrils preserve the biological properties of the brain-derived MSA strain. Detailed analyses of the in vivo studies demonstrate that both brain-derived and SAA-generated αSyn aggregates induce a similar disease, with comparable incubation periods, neuropathological damages and clinical manifestations. High-resolution cryo-EM analysis of SAA-amplified αSyn fibrils demonstrates that their conformation at the protofilament level closely resembles one of the αSyn filaments previously identified in MSA patient brains. Our findings suggest that SAA can amplify disease-specific misfolded αSyn conformation while preserving its main biological properties.
History
DepositionFeb 11, 2026Deposition site: RCSB / Processing site: RCSB
SupersessionFeb 25, 2026ID: 8UKA
Revision 1.0Feb 25, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2026Group: Author supporting evidence / Data collection / Category: em_admin / em_helical_entity
Item: _em_admin.last_update / _em_helical_entity.axial_symmetry
Revision 1.1Mar 4, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data collection / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_helical_entity / Data content type: EM metadata / EM metadata
Item: _em_admin.last_update / _em_helical_entity.axial_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-synuclein
X: Alpha-synuclein
U: Alpha-synuclein
C: Alpha-synuclein
W: Alpha-synuclein
E: Alpha-synuclein
B: Alpha-synuclein
Y: Alpha-synuclein
Z: Alpha-synuclein
D: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)66,07510
Polymers66,07510
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 6607.472 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli (E. coli) / References: UniProt: P37840
Has protein modificationN

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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: Alpha-synuclein protein filament / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 1.5 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenConc.: 1 mg/ml / Embedding 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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 49 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION5particle selection
2PHENIXdev_3965:model refinement
13RELION53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.42 ° / Axial rise/subunit: 2.41 Å / Axial symmetry: C1
3D reconstructionResolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 6698 / Symmetry type: HELICAL
RefinementHighest resolution: 3.18 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034650
ELECTRON MICROSCOPYf_angle_d0.6586280
ELECTRON MICROSCOPYf_dihedral_angle_d6.25686
ELECTRON MICROSCOPYf_chiral_restr0.059810
ELECTRON MICROSCOPYf_plane_restr0.002790

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