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

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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: C2
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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