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- PDB-6xyo: Multiple system atrophy Type I alpha-synuclein filament -

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Basic information

Entry
Database: PDB / ID: 6xyo
TitleMultiple system atrophy Type I alpha-synuclein filament
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / multiple system atrophy / alpha-synuclein filament
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 / regulation of synaptic vesicle recycling ...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 / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / positive regulation of neurotransmitter secretion / regulation of macrophage activation / negative regulation of dopamine metabolic process / SNARE complex assembly / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of thrombin-activated receptor signaling pathway / Lewy body / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / regulation of norepinephrine uptake / synaptic vesicle priming / transporter regulator activity / protein kinase inhibitor activity / dopamine uptake involved in synaptic transmission / synaptic vesicle transport / regulation of dopamine secretion / positive regulation of receptor recycling / positive regulation of exocytosis / mitochondrial ATP synthesis coupled electron transport / dynein complex binding / cuprous ion binding / nuclear outer membrane / synaptic vesicle exocytosis / response to magnesium ion / positive regulation of endocytosis / negative regulation of serotonin uptake / response to type II interferon / kinesin binding / cysteine-type endopeptidase inhibitor activity / synaptic vesicle endocytosis / regulation of presynapse assembly / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / supramolecular fiber organization / phospholipid metabolic process / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / axon terminus / response to interleukin-1 / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / regulation of microtubule cytoskeleton organization / SNARE binding / adult locomotory behavior / glutathione metabolic process / excitatory postsynaptic potential / protein tetramerization / protein sequestering activity / tubulin binding / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / synapse organization / regulation of long-term neuronal synaptic plasticity / receptor internalization / phospholipid binding / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / growth cone / actin binding / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / amyloid fibril formation / chemical synaptic transmission
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsSchweighauser, M. / Shi, Y. / Tarutani, A. / Kametani, F. / Murzin, A.G. / Ghetti, B. / Matsubara, T. / Tomita, T. / Ando, T. / Hasegawa, K. ...Schweighauser, M. / Shi, Y. / Tarutani, A. / Kametani, F. / Murzin, A.G. / Ghetti, B. / Matsubara, T. / Tomita, T. / Ando, T. / Hasegawa, K. / Murayama, S. / Yoshida, M. / Hasegawa, M. / Scheres, S.H.W. / Goedert, M.
Funding support United Kingdom, Japan, United States, 7items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
Innovative Medicines Initiative116060 United Kingdom
Japan Agency for Medical Research and Development (AMED)JP18ek0109391 Japan
Japan Agency for Medical Research and Development (AMED)JP18dm020719 Japan
National Institutes of Health/National Institute on Aging (NIH/NIA)P30AG010133 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)U01NS110437 United States
CitationJournal: Nature / Year: 2020
Title: Structures of α-synuclein filaments from multiple system atrophy.
Authors: Manuel Schweighauser / Yang Shi / Airi Tarutani / Fuyuki Kametani / Alexey G Murzin / Bernardino Ghetti / Tomoyasu Matsubara / Taisuke Tomita / Takashi Ando / Kazuko Hasegawa / Shigeo ...Authors: Manuel Schweighauser / Yang Shi / Airi Tarutani / Fuyuki Kametani / Alexey G Murzin / Bernardino Ghetti / Tomoyasu Matsubara / Taisuke Tomita / Takashi Ando / Kazuko Hasegawa / Shigeo Murayama / Mari Yoshida / Masato Hasegawa / Sjors H W Scheres / Michel Goedert /
Abstract: Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases. ...Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases. Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies, the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous α-synuclein inclusions in the human brain.
History
DepositionJan 30, 2020Deposition site: PDBE / Processing site: PDBE
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Structure visualization

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Structure viewerMolecule:
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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: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area53190 Å2
ΔGint-151 kcal/mol
Surface area28780 Å2

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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 natural source / Source: (natural) Homo sapiens (human) / 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: Sarkosyl-insoluble fractions from the putamen of multiple system atrophy brain
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
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
Image recordingElectron dose: 49.2 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_3580: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.44 ° / Axial rise/subunit: 4.72 Å / Axial symmetry: C1
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 120501 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0085510
ELECTRON MICROSCOPYf_angle_d0.6287425
ELECTRON MICROSCOPYf_dihedral_angle_d12.9973255
ELECTRON MICROSCOPYf_chiral_restr0.054950
ELECTRON MICROSCOPYf_plane_restr0.002935

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