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- PDB-8adu: Lipidic alpha-synuclein fibril - polymorph L1A -

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Basic information

Entry
Database: PDB / ID: 8adu
TitleLipidic alpha-synuclein fibril - polymorph L1A
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / amyloid fibril
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 / regulation of reactive oxygen species biosynthetic process ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / dopamine biosynthetic process / dopamine uptake involved in synaptic transmission / response to iron(II) ion / negative regulation of dopamine metabolic process / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of thrombin-activated receptor signaling pathway / Lewy body / negative regulation of microtubule polymerization / synaptic vesicle priming / regulation of norepinephrine uptake / transporter regulator activity / protein kinase inhibitor activity / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle transport / regulation of dopamine secretion / positive regulation of receptor recycling / cuprous ion binding / positive regulation of exocytosis / nuclear outer membrane / dynein complex binding / synaptic transmission, dopaminergic / synaptic vesicle exocytosis / response to magnesium ion / positive regulation of endocytosis / negative regulation of serotonin uptake / kinesin binding / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / cellular response to fibroblast growth factor stimulus / response to type II interferon / cellular response to epinephrine stimulus / inclusion body / Hsp70 protein binding / response to interleukin-1 / axon terminus / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / enzyme inhibitor activity / regulation of microtubule cytoskeleton organization / SNARE binding / glutathione metabolic process / protein tetramerization / protein sequestering activity / phosphoprotein binding / receptor internalization / tubulin binding / microglial cell activation / ferrous iron binding / phospholipid binding / PKR-mediated signaling / synapse organization / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / actin cytoskeleton / synaptic vesicle membrane / growth cone / actin binding / cellular response to oxidative stress / response to lipopolysaccharide / histone binding / cell cortex / microtubule binding / amyloid fibril formation / negative regulation of neuron apoptotic process / mitochondrial outer membrane / lysosome / oxidoreductase activity / mitochondrial inner membrane / transcription cis-regulatory region binding / positive regulation of apoptotic process / ribosome / mitochondrial matrix / Amyloid fiber formation / copper ion binding / protein domain specific binding / axon / neuronal cell body / calcium ion binding
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.24 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / struct_ncs_dom_lim
Item: _em_admin.last_update / _struct_ncs_dom_lim.beg_auth_asym_id ..._em_admin.last_update / _struct_ncs_dom_lim.beg_auth_asym_id / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_auth_seq_id / _struct_ncs_dom_lim.end_auth_asym_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_auth_seq_id

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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


Theoretical massNumber of molelcules
Total (without water)72,3815
Polymers72,3815
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 (eV)
d_1ens_1chain "E"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "D"
d_5ens_1chain "A"

NCS domain segments:

Component-ID: 1 / Ens-ID: ens_1 / Beg auth comp-ID: MET / Beg label comp-ID: MET / End auth comp-ID: GLN / End label comp-ID: GLN / Auth seq-ID: 1 - 99 / Label seq-ID: 1 - 99

Dom-IDAuth asym-IDLabel asym-ID
d_1EE
d_2BB
d_3CC
d_4DD
d_5AA

NCS oper:
IDCodeMatrixVector
1given(0.99874278395, -0.0501283493834), (0.0501283494436, 0.998742783977), (0.999999999934)6.74494562324, -6.41490722992, -14.0703646812
2given(0.99944108791, -0.0334292043172), (0.0334292043797, 0.999441087936), (0.999999999932)4.46156191351, -4.31483093889, -9.38036833283
3given(0.999860235779, -0.0167185171758), (0.0167185172364, 0.999860235804), (0.999999999935)2.21322415837, -2.17659650556, -4.69036733308
4given(0.997765400935, -0.0668147034483), (0.06681470351, 0.997765400963), (0.999999999932)9.06334716517, -8.4766915867, -18.7603629671

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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.: 5
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 L1A / 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: 42.72 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: -0.95 ° / Axial rise/subunit: 4.69 Å / Axial symmetry: C1
3D reconstructionResolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 13641 / Symmetry type: HELICAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 60.81 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00683475
ELECTRON MICROSCOPYf_angle_d0.78414660
ELECTRON MICROSCOPYf_chiral_restr0.0678580
ELECTRON MICROSCOPYf_plane_restr0.0028585
ELECTRON MICROSCOPYf_dihedral_angle_d5.6547495
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2EELECTRON MICROSCOPYNCS constraints0.00065769280073
ens_1d_3EELECTRON MICROSCOPYNCS constraints0.000657980970102
ens_1d_4EELECTRON MICROSCOPYNCS constraints0.000657832787603
ens_1d_5EELECTRON MICROSCOPYNCS constraints0.000650762264243

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