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- PDB-6pes: Cryo-EM structure of alpha-synuclein H50Q Wide Fibril -

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Basic information

Entry
Database: PDB / ID: 6pes
TitleCryo-EM structure of alpha-synuclein H50Q Wide Fibril
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / Alpha-synuclein / amyloid / H50Q / hereditary mutation / 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 / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / 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 / regulation of dopamine secretion / dynein complex binding / mitochondrial ATP synthesis coupled electron transport / 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 / growth cone / actin binding / cellular response to oxidative stress / neuron apoptotic process / cell cortex / response to lipopolysaccharide / histone binding / microtubule binding / chemical synaptic transmission / molecular adaptor activity / 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: 3.6 Å
AuthorsBoyer, D.R. / Li, B. / Sawaya, M.R. / Jiang, L. / Eisenberg, D.S.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG054022 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG061847 United States
Department of Energy (DOE, United States)DE-FC02-02ER63421 United States
CitationJournal: Nat Struct Mol Biol / Year: 2019
Title: Structures of fibrils formed by α-synuclein hereditary disease mutant H50Q reveal new polymorphs.
Authors: David R Boyer / Binsen Li / Chuanqi Sun / Weijia Fan / Michael R Sawaya / Lin Jiang / David S Eisenberg /
Abstract: Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, with hereditary mutations in α-synuclein ...Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, with hereditary mutations in α-synuclein linked to the first two of these conditions. Seeing the changes to the structures of amyloid fibrils bearing these mutations may help to understand these diseases. To this end, we determined the cryo-EM structures of α-synuclein fibrils containing the H50Q hereditary mutation. We find that the H50Q mutation results in two previously unobserved polymorphs of α-synuclein: narrow and wide fibrils, formed from either one or two protofilaments, respectively. These structures recapitulate conserved features of the wild-type fold but reveal new structural elements, including a previously unobserved hydrogen-bond network and surprising new protofilament arrangements. The structures of the H50Q polymorphs help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells and greater cytotoxicity that we observe for H50Q compared to wild-type α-synuclein.
History
DepositionJun 20, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2019Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2019Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2019Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2019Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2019Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2019Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2019Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2019Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2May 21, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
A: Alpha-synuclein
B: Alpha-synuclein
C: Alpha-synuclein
D: Alpha-synuclein
E: Alpha-synuclein
W: Alpha-synuclein
V: Alpha-synuclein
X: Alpha-synuclein
Y: Alpha-synuclein
Z: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)144,66110
Polymers144,66110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Alpha-synuclein / Non-A beta component of AD amyloid / Non-A4 component of amyloid precursor / NACP


Mass: 14466.091 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 (E. coli) / References: UniProt: P37840
Has protein modificationN

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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 amyloid fibril with H50Q hereditary mutation - Wide Fibril polymorph
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7
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
Image recordingElectron dose: 26 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_3360: / Classification: refinement
EM software
IDNameVersionCategory
1RELION2particle selection
2Leginon3image acquisition
4CTFFIND4.1.8CTF correction
8PHENIXmodel refinement
10RELION2initial Euler assignment
11RELION2final Euler assignment
13RELION23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.83 ° / Axial rise/subunit: 4.82 Å / Axial symmetry: C1
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 28016 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0094045
ELECTRON MICROSCOPYf_angle_d0.6765465
ELECTRON MICROSCOPYf_dihedral_angle_d8.3162385
ELECTRON MICROSCOPYf_chiral_restr0.06725
ELECTRON MICROSCOPYf_plane_restr0.0061097

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