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- PDB-7xo3: Type 1C alpha-synuclein fibril seeded by cerebrospinal fluid from... -

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Basic information

Entry
Database: PDB / ID: 7xo3
TitleType 1C alpha-synuclein fibril seeded by cerebrospinal fluid from a mid-to-late stage (mid-PD-4) Parkinson's disease patient
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / amyloid fibril
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 hydrogen peroxide catabolic process / positive regulation of SNARE complex assembly ...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 hydrogen peroxide catabolic process / positive regulation of SNARE complex assembly / supramolecular fiber / regulation of reactive oxygen species biosynthetic process / regulation of glutamate secretion / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of transporter activity / regulation of synaptic vesicle recycling / negative regulation of exocytosis / response to iron(II) ion / regulation of norepinephrine uptake / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of locomotion / SNARE complex assembly / synaptic vesicle priming / positive regulation of inositol phosphate biosynthetic process / dopamine uptake involved in synaptic transmission / negative regulation of histone acetylation / regulation of macrophage activation / synaptic vesicle transport / negative regulation of microtubule polymerization / dynein complex binding / positive regulation of receptor recycling / mitochondrial ATP synthesis coupled electron transport / regulation of dopamine secretion / response to magnesium ion / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / synaptic vesicle exocytosis / cuprous ion binding / positive regulation of endocytosis / positive regulation of exocytosis / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / alpha-tubulin binding / kinesin binding / regulation of presynapse assembly / synaptic vesicle endocytosis / supramolecular fiber organization / negative regulation of serotonin uptake / axon terminus / phospholipid metabolic process / localization / regulation of neuron death / cellular response to epinephrine stimulus / excitatory postsynaptic potential / SNARE binding / inclusion body / adult locomotory behavior / response to interleukin-1 / Hsp70 protein binding / long-term synaptic potentiation / positive regulation of release of sequestered calcium ion into cytosol / fatty acid metabolic process / synapse organization / cellular response to copper ion / microglial cell activation / regulation of long-term neuronal synaptic plasticity / regulation of transmembrane transporter activity / ferrous iron binding / positive regulation of protein serine/threonine kinase activity / protein destabilization / phospholipid binding / protein tetramerization / synaptic vesicle membrane / negative regulation of neuron death / tau protein binding / receptor internalization / phosphoprotein binding / negative regulation of protein kinase activity / positive regulation of inflammatory response / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron death / activation of cysteine-type endopeptidase activity involved in apoptotic process / cell cortex / actin cytoskeleton / cellular response to oxidative stress / growth cone / actin binding / postsynapse / chemical synaptic transmission / histone binding / neuron apoptotic process / positive regulation of peptidyl-serine phosphorylation / response to lipopolysaccharide / amyloid fibril formation / negative regulation of neuron apoptotic process / lysosome / molecular adaptor activity
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsFan, Y. / Sun, Y.P. / Wang, J. / Liu, C.
Funding support China, 1items
OrganizationGrant numberCountry
Not funded China
CitationJournal: Structure / Year: 2023
Title: Conformational change of α-synuclein fibrils in cerebrospinal fluid from different clinical phases of Parkinson's disease.
Authors: Yun Fan / Yunpeng Sun / Wenbo Yu / Youqi Tao / Wencheng Xia / Yiqi Liu / Qinyue Zhao / Yilin Tang / Yimin Sun / Fengtao Liu / Qin Cao / Jianjun Wu / Cong Liu / Jian Wang / Dan Li /
Abstract: α-Synuclein (α-syn) has been shown to form various conformational fibrils associated with different synucleinopathies. But whether the conformation of α-syn fibrils changes during disease ...α-Synuclein (α-syn) has been shown to form various conformational fibrils associated with different synucleinopathies. But whether the conformation of α-syn fibrils changes during disease progression is unclear. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) staged in preclinical PD (pre-PD), middle- to late-stage PD (mid-PD), and late-stage PD (late-PD). Our results show that α-syn fibrils derived from the late-PD patient are most potent in inducing endogenous α-syn aggregation in primary neurons, followed by the mid-PD and pre-PD fibrils. By using cryo-electron microscopy, we further determined the high-resolution structures of the CSF-amplified fibrils. The structures exhibit remarkable differences in a minor but significant population of conformational species in different staged samples. Our work demonstrates structural and pathological differences between α-syn fibrils derived from PD patients at a spectrum of clinical stages, which suggests potential conformational transition of α-syn fibrils during the progression of PD.
History
DepositionApr 30, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 30, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation_author.name
Revision 1.2Jan 25, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Alpha-synuclein
A: Alpha-synuclein
E: Alpha-synuclein
C: Alpha-synuclein
F: Alpha-synuclein
D: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)86,8576
Polymers86,8576
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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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.: 6
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

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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: Type 1C alpha-synuclein fibril seeded by cerebrospinal fluid from a mid-to-late stage (mid-PD-4) Parkinson's disease patient
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 6.5
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: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 179.43 ° / Axial rise/subunit: 2.41 Å / Axial symmetry: C1
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 120165 / Symmetry type: HELICAL

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