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- PDB-8ads: Lipidic alpha-synuclein fibril - polymorph L2B -

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Basic information

Entry
Database: PDB / ID: 8ads
TitleLipidic alpha-synuclein fibril - polymorph L2B
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 acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / SNARE complex assembly / regulation of locomotion / positive regulation of neurotransmitter secretion / negative regulation of dopamine metabolic process / positive regulation of inositol phosphate biosynthetic process / regulation of macrophage activation / regulation of norepinephrine uptake / negative regulation of microtubule polymerization / synaptic vesicle transport / transporter regulator activity / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / mitochondrial ATP synthesis coupled electron transport / regulation of dopamine secretion / dynein complex binding / negative regulation of thrombin-activated receptor signaling pathway / positive regulation of receptor recycling / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of endocytosis / positive regulation of exocytosis / synaptic vesicle exocytosis / kinesin binding / synaptic vesicle endocytosis / enzyme inhibitor activity / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / response to type II interferon / regulation of presynapse assembly / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / phospholipid metabolic process / cellular response to fibroblast growth factor stimulus / inclusion body / axon terminus / Hsp70 protein binding / cellular response to epinephrine stimulus / response to interleukin-1 / regulation of microtubule cytoskeleton organization / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / SNARE binding / excitatory postsynaptic potential / protein tetramerization / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / regulation of long-term neuronal synaptic plasticity / synapse organization / protein destabilization / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / terminal bouton / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / molecular adaptor activity / chemical synaptic transmission / amyloid fibril formation / negative regulation of neuron apoptotic process / mitochondrial outer membrane / oxidoreductase activity
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsFrieg, B. / Antonschmidt, L. / Dienemann, C. / Geraets, J.A. / Najbauer, E.E. / Matthes, D. / de Groot, B.L. / Andreas, L.B. / Becker, S. / Griesinger, C. / Schroeder, G.F.
Funding support Germany, 4items
OrganizationGrant numberCountry
Max Planck Society Germany
German Research Foundation (DFG)2067/1-390729940 Germany
German Research Foundation (DFG)397022504 Germany
Helmholtz Association Germany
CitationJournal: Nat Commun / Year: 2022
Title: The 3D structure of lipidic fibrils of α-synuclein.
Authors: Benedikt Frieg / Leif Antonschmidt / Christian Dienemann / James A Geraets / Eszter E Najbauer / Dirk Matthes / Bert L de Groot / Loren B Andreas / Stefan Becker / Christian Griesinger / Gunnar F Schröder /
Abstract: α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson's disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal ...α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson's disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal inclusions called Lewy bodies. Studies on the composition of Lewy bodies extracted postmortem from brain tissue of Parkinson's patients revealed that lipids and membranous organelles are also a significant component. Interactions between α-synuclein and lipids have been previously identified as relevant for Parkinson's disease pathology, however molecular insights into their interactions have remained elusive. Here we present cryo-electron microscopy structures of six α-synuclein fibrils in complex with lipids, revealing specific lipid-fibril interactions. We observe that phospholipids promote an alternative protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities of the fibrils. Together with our previous studies, these structures also indicate a mechanism for fibril-induced lipid extraction, which is likely to be involved in the development of α-synucleinopathies. Specifically, one potential mechanism for the cellular toxicity is the disruption of intracellular vesicles mediated by fibrils and oligomers, and therefore the modulation of these interactions may provide a promising strategy for future therapeutic interventions.
History
DepositionJul 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jul 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
B: Alpha-synuclein
C: Alpha-synuclein
D: Alpha-synuclein
E: Alpha-synuclein
F: Alpha-synuclein
G: Alpha-synuclein
H: Alpha-synuclein
I: Alpha-synuclein
J: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)144,76110
Polymers144,76110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "G"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "D"
d_5ens_1chain "E"
d_6ens_1chain "F"
d_7ens_1chain "A"
d_8ens_1chain "H"
d_9ens_1chain "I"
d_10ens_1chain "J"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLYLYSG1 - 75
d_21ens_1GLYLYSB1 - 75
d_31ens_1GLYLYSC1 - 75
d_41ens_1GLYLYSD1 - 75
d_51ens_1GLYLYSE1 - 75
d_61ens_1GLYLYSF1 - 75
d_71ens_1GLYLYSA1 - 75
d_81ens_1GLYLYSH1 - 75
d_91ens_1GLYLYSI1 - 75
d_101ens_1GLYLYSJ1 - 75

NCS oper:
IDCodeMatrixVector
1given(-0.62910675394, -0.777046589347, 0.0205740159267), (-0.777224774906, 0.629222104681, -0.00109190346073), (-0.0120971657431, -0.0166775587393, -0.99978773628)312.995309517, 144.208787608, 292.326695901
2given(-0.618913394921, -0.785180701964, 0.0209158994882), (-0.785374998296, 0.619017551425, -0.00183931485945), (-0.0115031143545, -0.0175652011289, -0.999779546735)312.749931953, 146.696007622, 287.673565477
3given(-0.608616003095, -0.793179954632, 0.0212631217368), (-0.793390065597, 0.608708103921, -0.00257837808855), (-0.0108979167005, -0.0184391917163, -0.999770589496)312.474349385, 149.174209526, 283.017015705
4given(-0.598213751292, -0.801044789796, 0.02162296247), (-0.801270613921, 0.598292917871, -0.00331476880357), (-0.0102815870297, -0.0193087846938, -0.999760701269)312.167455572, 151.644495121, 278.358448381
5given(0.999914713808, -0.0130546572238, -0.000375545148922), (0.013054928041, 0.999914515816, 0.000727951920492), (0.000366009882954, -0.000732792551141, 0.999999664526)1.74728052092, -1.81295711905, -4.64292556147
6given(-0.639190931082, -0.768781524732, 0.0202465022416), (-0.768943524542, 0.639316618873, -0.000341903862376), (-0.0126810759845, -0.0157869586414, -0.999794960104)313.209001453, 141.714738235, 296.978133948
7given(0.999914620963, 0.0130619747827, 0.000368237741421), (-0.0130617018752, 0.999914422911, -0.000734029340507), (-0.000377794101443, 0.000729156858191, 0.999999662801)-1.72323261663, 1.83340873409, 4.64508013639
8given(0.999658630959, 0.0261170169629, 0.000723169139641), (-0.0261159336815, 0.999657841569, -0.00146894418518), (-0.000761286141424, 0.00144955649582, 0.999998659614)-3.4194003188, 3.68439186358, 9.29210173164
9given(0.999231929314, 0.0391715173439, 0.00106942458381), (-0.0391690774428, 0.999230143673, -0.00221435050587), (-0.00115534074977, 0.00217076135382, 0.999996976487)-5.09018373272, 5.55546810322, 13.9404243995

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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.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli BL21(DE3) (bacteria) / 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: Lipidic alpha-synuclein fibril - polymorph L2B / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4
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: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.82 ° / Axial rise/subunit: 4.69 Å / Axial symmetry: C1
3D reconstructionResolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 20388 / Symmetry type: HELICAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 70.85 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00335180
ELECTRON MICROSCOPYf_angle_d0.43926980
ELECTRON MICROSCOPYf_chiral_restr0.0555920
ELECTRON MICROSCOPYf_plane_restr0.0012860
ELECTRON MICROSCOPYf_dihedral_angle_d4.5201740
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2GELECTRON MICROSCOPYNCS constraints0.000702129794347
ens_1d_3GELECTRON MICROSCOPYNCS constraints0.000706927086283
ens_1d_4GELECTRON MICROSCOPYNCS constraints0.000716288419909
ens_1d_5GELECTRON MICROSCOPYNCS constraints0.000708814207419
ens_1d_6GELECTRON MICROSCOPYNCS constraints0.000715915288422
ens_1d_7GELECTRON MICROSCOPYNCS constraints0.000701856000358
ens_1d_8GELECTRON MICROSCOPYNCS constraints0.000728048641506
ens_1d_9GELECTRON MICROSCOPYNCS constraints0.000709135982193
ens_1d_10GELECTRON MICROSCOPYNCS constraints0.000713778036752

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