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- EMDB-33334: Minor polymorph in alpha-synuclein fibril seeded by cerebrospinal... -

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Basic information

Entry
Database: EMDB / ID: EMD-33334
TitleMinor polymorph in alpha-synuclein fibril seeded by cerebrospinal fluid from a mid-to-late stage (mid-PD-4) Parkinson's disease patient
Map data
Sample
  • Organelle or cellular component: Minor polymorph in alpha-synuclein fibril seeded by cerebrospinal fluid from a mid-to-late stage (mid-PD-4) Parkinson's disease patient
    • Protein or peptide: Alpha-synuclein
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)
Methodhelical reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsFan Y / Sun YP / Wang J / Liu C
Funding support China, 7 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32170683 China
National Natural Science Foundation of China (NSFC)82188101 China
National Natural Science Foundation of China (NSFC)31872716 China
National Natural Science Foundation of China (NSFC)82171421 China
National Natural Science Foundation of China (NSFC)91949118 China
National Natural Science Foundation of China (NSFC)81771372 China
National Natural Science Foundation of China (NSFC)U1932204 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, 2022-
Header (metadata) releaseNov 30, 2022-
Map releaseNov 30, 2022-
UpdateJan 25, 2023-
Current statusJan 25, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33334.png

Downloads & links

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Map

FileDownload / File: emd_33334.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 288 pix.
= 305.28 Å		1.06 Å/pix.
x 288 pix.
= 305.28 Å		1.06 Å/pix.
x 288 pix.
= 305.28 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
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Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.02728923 - 0.079338424
Average (Standard dev.)0.00076892646 (±0.0038658355)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 305.27997 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33334_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_33334_half_map_2.map
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Sample components

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Entire : Minor polymorph in alpha-synuclein fibril seeded by cerebrospinal...

EntireName: Minor polymorph in alpha-synuclein fibril seeded by cerebrospinal fluid from a mid-to-late stage (mid-PD-4) Parkinson's disease patient
Components
  • Organelle or cellular component: Minor polymorph in alpha-synuclein fibril seeded by cerebrospinal fluid from a mid-to-late stage (mid-PD-4) Parkinson's disease patient
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Minor polymorph in alpha-synuclein fibril seeded by cerebrospinal...

SupramoleculeName: Minor polymorph in 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 / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 6.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6ssx

Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 2.42 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.34 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 14416
FSC plot (resolution estimation)

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