|Entry||Database: PDB / ID: 7xo2|
|Title||Minor polymorph in alpha-synuclein fibril seeded by cerebrospinal fluid from a mid-to-late stage (mid-PD-4) Parkinson's disease patient|
|Keywords||PROTEIN 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
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3 Å|
|Authors||Fan, Y. / Sun, Y.P. / Wang, J. / Liu, C.|
|Funding support|| China, 7items |
|Citation||Journal: 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.
|Structure viewer||Molecule: |
Downloads & links
|Noncrystallographic symmetry (NCS)||NCS domain: |
NCS domain segments:
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
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction|
|Component||Name: 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 / Entity ID: all / Source: RECOMBINANT
|Molecular weight||Experimental value: NO|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Escherichia coli (E. coli)|
|Buffer solution||pH: 6.5|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm|
|Image recording||Electron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)|
|CTF correction||Type: NONE|
|Helical symmerty||Angular rotation/subunit: 179.34 ° / Axial rise/subunit: 2.42 Å / Axial symmetry: C1|
|3D reconstruction||Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14416 / Symmetry type: HELICAL|
|Refinement||Cross valid method: NONE|
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
|Displacement parameters||Biso mean: 44.61 Å2|
|Refine LS restraints|
|Refine LS restraints NCS|
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