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- PDB-8h03: Major polymorph in alpha-synuclein fibril seeded by cerebrospinal... -

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Basic information

Entry
Database: PDB / ID: 8h03
TitleMajor polymorph in alpha-synuclein fibril seeded by cerebrospinal fluid from a preclinical 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 SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process ...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 SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / negative regulation of transporter activity / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / regulation of synaptic vesicle recycling / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / regulation of norepinephrine uptake / dopamine biosynthetic process / SNARE complex assembly / positive regulation of neurotransmitter secretion / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / regulation of macrophage activation / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / positive regulation of endocytosis / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / positive regulation of exocytosis / synaptic vesicle exocytosis / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / kinesin binding / alpha-tubulin binding / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / localization / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / Hsp70 protein binding / cellular response to epinephrine stimulus / excitatory postsynaptic potential / response to interleukin-1 / adult locomotory behavior / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / fatty acid metabolic process / long-term synaptic potentiation / regulation of transmembrane transporter activity / ferrous iron binding / synapse organization / phospholipid binding / protein tetramerization / phosphoprotein binding / microglial cell activation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / tau protein binding / protein destabilization / PKR-mediated signaling / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of protein serine/threonine kinase activity / receptor internalization / synaptic vesicle membrane / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / cellular response to oxidative stress / actin binding / cell cortex / growth cone / histone binding / chemical synaptic transmission / postsynapse / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / lysosome / oxidoreductase activity / molecular adaptor activity / transcription cis-regulatory region binding
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsFan, Y. / Sun, Y.P. / Wang, J. / Liu, C.
Funding support China, 7items
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
DepositionSep 28, 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
  • Evidence: amyloid fibril consisting of cross-beta motif with an ~0.48 nm repeat running down the fibril axis
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "D"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "A"
d_5ens_1chain "E"
d_6ens_1chain "F"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLYLYSF1 - 61
d_21ens_1GLYLYSA1 - 61
d_31ens_1GLYLYSD1 - 61
d_41ens_1GLYLYSB1 - 61
d_51ens_1GLYLYSC1 - 61
d_61ens_1GLYLYSE1 - 61

NCS oper:
IDCodeMatrixVector
1given(-0.999957913463, 0.00909931917669, -0.00117204675652), (-0.0090953519106, -0.999953035348, -0.00334689001925), (-0.00120244613229, -0.00333608898253, 0.999993712297)337.825631308, 341.338119584, -1.75155747243
2given(0.999293295309, -0.0375881860116, 0.000195504330021), (0.0375883458962, 0.999292911114, -0.000891094718333), (-0.000161871457056, 0.000897813661897, 0.999999583864)6.56181204058, -6.09686602631, -9.74519281308
3given(0.99982322905, -0.0188011391414, 0.000166792307881), (0.0188011408386, 0.999823242893, -8.61339687263E-6), (-0.000166600884482, 1.17477599455E-5, 0.999999986053)3.22705325866, -3.150741694, -4.81074099158
4given(-0.999576312046, 0.0290849431223, -0.00112360154142), (-0.0290871992501, -0.999574782558, 0.00204668366294), (-0.00106359608852, 0.00207849892964, 0.999997274299)334.366247214, 343.698059851, -7.31849056166
5given(-0.999962228679, -0.00862535836045, -0.00106977041492), (0.00862664623819, -0.999962063552, -0.00120516827798), (-0.00105933482335, -0.0012143512881, 0.999998701579)340.89525488, 337.938996122, 2.75585436803

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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: Major polymorph in alpha-synuclein fibril seeded by cerebrospinal fluid from a preclinical 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: OTHER
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

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 179.45 ° / Axial rise/subunit: 2.44 Å / Axial symmetry: C1
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 69047 / Symmetry type: HELICAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 42.7 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00152508
ELECTRON MICROSCOPYf_angle_d0.43383396
ELECTRON MICROSCOPYf_chiral_restr0.0522450
ELECTRON MICROSCOPYf_plane_restr0.0015420
ELECTRON MICROSCOPYf_dihedral_angle_d3.9722366
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2FELECTRON MICROSCOPYNCS constraints1.37567781401E-13
ens_1d_3FELECTRON MICROSCOPYNCS constraints1.14671239972E-10
ens_1d_4FELECTRON MICROSCOPYNCS constraints1.25775576176E-10
ens_1d_5FELECTRON MICROSCOPYNCS constraints7.6992384456E-11
ens_1d_6FELECTRON MICROSCOPYNCS constraints9.10562289619E-11

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