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- PDB-8bqw: Cryo-EM structure of alpha-synuclein filaments doublet from Juven... -

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Basic information

Entry
Database: PDB / ID: 8bqw
TitleCryo-EM structure of alpha-synuclein filaments doublet from Juvenile-onset synucleinopathy
Components
  • Alpha-synuclein
  • Unknown protein
KeywordsPROTEIN FIBRIL / alpha-synuclein / amyloid / fibril / insertion / juvenile-onset synucleinopathy (JOS) / synucleinopathy
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 / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / 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 / regulation of norepinephrine uptake / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of macrophage activation / negative regulation of microtubule polymerization / dopamine uptake involved in synaptic transmission / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / synaptic vesicle exocytosis / positive regulation of exocytosis / kinesin binding / positive regulation of endocytosis / mitochondrial ATP synthesis coupled electron transport / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / regulation of presynapse assembly / synaptic vesicle endocytosis / negative regulation of serotonin uptake / alpha-tubulin binding / localization / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / cellular response to epinephrine stimulus / Hsp70 protein binding / 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 / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / negative regulation of protein kinase activity / protein destabilization / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / ferrous iron binding / tau protein binding / PKR-mediated signaling / positive regulation of protein serine/threonine kinase activity / receptor internalization / phospholipid binding / 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 / actin binding / cell cortex / histone binding / cellular response to oxidative stress / growth cone / postsynapse / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / molecular adaptor activity / oxidoreductase activity / lysosome / 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: 2.3 Å
AuthorsYang, Y. / Garringer, J.H. / Shi, Y. / Lovestam, S. / Peak-Chew, S.Y. / Zhang, X.J. / Kotecha, A. / Bacioglu, M. / Koto, A. / Takao, M. ...Yang, Y. / Garringer, J.H. / Shi, Y. / Lovestam, S. / Peak-Chew, S.Y. / Zhang, X.J. / Kotecha, A. / Bacioglu, M. / Koto, A. / Takao, M. / Spillantini, G.M. / Ghetti, B. / Vidal, R. / Murzin, G.A. / Scheres, H.W.S. / Goedert, M.
Funding support United Kingdom, United States, 4items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 to M.G. United Kingdom
Alzheimers Research UK (ARUK) United Kingdom
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
CitationJournal: Acta Neuropathol / Year: 2023
Title: New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy.
Authors: Yang Yang / Holly J Garringer / Yang Shi / Sofia Lövestam / Sew Peak-Chew / Xianjun Zhang / Abhay Kotecha / Mehtap Bacioglu / Atsuo Koto / Masaki Takao / Maria Grazia Spillantini / ...Authors: Yang Yang / Holly J Garringer / Yang Shi / Sofia Lövestam / Sew Peak-Chew / Xianjun Zhang / Abhay Kotecha / Mehtap Bacioglu / Atsuo Koto / Masaki Takao / Maria Grazia Spillantini / Bernardino Ghetti / Ruben Vidal / Alexey G Murzin / Sjors H W Scheres / Michel Goedert /
Abstract: A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This ...A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.
History
DepositionJan 18, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2023Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 3, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-synuclein
C: Alpha-synuclein
B: Unknown protein
D: Unknown protein


Theoretical massNumber of molelcules
Total (without water)30,5204
Polymers30,5204
Non-polymers00
Water1629
1
A: Alpha-synuclein
C: Alpha-synuclein
B: Unknown protein
D: Unknown protein
x 5


Theoretical massNumber of molelcules
Total (without water)152,60120
Polymers152,60120
Non-polymers00
Water18010
TypeNameSymmetry operationNumber
point symmetry operation4
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2generate(0.999722, -0.023578), (0.023578, 0.999722), (1)2.21993, -2.16819, -4.75928
3generate(0.999722, 0.023578), (-0.023578, 0.999722), (1)-2.1682, 2.21993, 4.75928

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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.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P37840
#2: Protein/peptide Unknown protein


Mass: 783.958 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / Source method: isolated from a natural source / Formula: H2O

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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 doublet filament extracted from the human brain with JOS
Type: TISSUE / Entity ID: #1-#2 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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 FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0352 / Classification: refinement
EM software
IDNameVersionCategory
1RELIONparticle selection
2EPUimage acquisition
4RELIONCTF correction
7Cootmodel fitting
9RELION4initial Euler assignment
10RELIONfinal Euler assignment
11RELIONclassification
12RELION43D reconstruction
13REFMACmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.11 ° / Axial rise/subunit: 4.71 Å / Axial symmetry: C2
3D reconstructionResolution: 2.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45038 / Symmetry type: HELICAL
Atomic model buildingDetails: servalcat
RefinementResolution: 2.3→149.76 Å / Cor.coef. Fo:Fc: 0.707 / SU B: 5.166 / SU ML: 0.121 / ESU R: 0.11
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.46273 --
obs0.46273 113357 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 52.265 Å2
Refinement stepCycle: 1 / Total: 1159
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0030.0121150
ELECTRON MICROSCOPYr_bond_other_d00.0161176
ELECTRON MICROSCOPYr_angle_refined_deg0.7831.631550
ELECTRON MICROSCOPYr_angle_other_deg0.2841.5752708
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.2895166
ELECTRON MICROSCOPYr_dihedral_angle_2_deg
ELECTRON MICROSCOPYr_dihedral_angle_3_deg8.42310184
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0340.2204
ELECTRON MICROSCOPYr_gen_planes_refined0.0030.021292
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02188
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it2.4335.258682
ELECTRON MICROSCOPYr_mcbond_other2.4335.258682
ELECTRON MICROSCOPYr_mcangle_it4.1127.802842
ELECTRON MICROSCOPYr_mcangle_other4.117.821843
ELECTRON MICROSCOPYr_scbond_it2.9185.35468
ELECTRON MICROSCOPYr_scbond_other2.9155.372469
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other4.9927.921709
ELECTRON MICROSCOPYr_long_range_B_refined8.80958.21016
ELECTRON MICROSCOPYr_long_range_B_other8.80558.3731017
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.066 8333 -
obs--100 %

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