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- PDB-9cda: Structure of type I-2 alpha-synuclein filament from multiple syst... -

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Basic information

Entry
Database: PDB / ID: 9cda
TitleStructure of type I-2 alpha-synuclein filament from multiple system atrophy
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / fibril / synuclein
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 / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / mitochondrial membrane organization / 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 / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of thrombin-activated receptor signaling pathway / Lewy body / regulation of locomotion / negative regulation of microtubule polymerization / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of norepinephrine uptake / transporter regulator activity / protein kinase inhibitor activity / synaptic vesicle transport / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / positive regulation of receptor recycling / positive regulation of exocytosis / cuprous ion binding / nuclear outer membrane / mitochondrial ATP synthesis coupled electron transport / dynein complex binding / synaptic vesicle exocytosis / response to magnesium ion / positive regulation of endocytosis / negative regulation of serotonin uptake / response to type II interferon / cysteine-type endopeptidase inhibitor activity / kinesin binding / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / phospholipid metabolic process / supramolecular fiber organization / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / cellular response to epinephrine stimulus / inclusion body / Hsp70 protein binding / enzyme inhibitor activity / response to interleukin-1 / axon terminus / 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 / protein tetramerization / protein sequestering activity / tubulin binding / phosphoprotein binding / excitatory postsynaptic potential / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / phospholipid binding / synapse organization / receptor internalization / regulation of long-term neuronal synaptic plasticity / 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: 3.3 Å
AuthorsYan, N.L. / Candido, F. / Tse, E. / Melo, A.A. / Southworth, D.R. / Merz, G.E.
Funding support United States, 3items
OrganizationGrant numberCountry
Other privateHU0001-21-2-065, subaward 5802 United States
Other private United States
Other private United States
CitationJournal: FEBS Lett / Year: 2025
Title: Cryo-EM structure of a novel α-synuclein filament subtype from multiple system atrophy.
Authors: Nicholas L Yan / Francisco Candido / Eric Tse / Arthur A Melo / Stanley B Prusiner / Daniel A Mordes / Daniel R Southworth / Nick A Paras / Gregory E Merz /
Abstract: Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by accumulation of α-synuclein cross-β amyloid filaments in the brain. Previous structural studies of these ...Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by accumulation of α-synuclein cross-β amyloid filaments in the brain. Previous structural studies of these filaments by cryo-electron microscopy (cryo-EM) revealed three discrete folds distinct from α-synuclein filaments associated with other neurodegenerative diseases. Here, we use cryo-EM to identify a novel, low-populated MSA filament subtype (designated Type I) in addition to a predominant class comprising MSA Type II filaments. The 3.3-Å resolution structure of the Type I filament reveals a fold consisting of two asymmetric protofilaments, one of which adopts a novel structure that is chimeric between two previously reported protofilaments. These results further define MSA-specific folds of α-synuclein filaments and have implications for designing MSA diagnostics and therapeutics.
History
DepositionJun 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
K: Alpha-synuclein
L: Alpha-synuclein
M: Alpha-synuclein
N: Alpha-synuclein
Q: Alpha-synuclein
R: Alpha-synuclein
S: Alpha-synuclein
T: Alpha-synuclein
U: Alpha-synuclein
V: Alpha-synuclein
W: Alpha-synuclein
X: Alpha-synuclein
Y: Alpha-synuclein
Z: Alpha-synuclein
a: Alpha-synuclein
b: Alpha-synuclein
O: Alpha-synuclein
P: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)260,57018
Polymers260,57018
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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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.: 18 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum / 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: Type I-2 alpha-synuclein filament from multiple system atrophy
Type: COMPLEX / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum
Buffer solutionpH: 7.4
Buffer componentConc.: 30 mM / Name: Tris-HCl
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: Wait time 30s, blot time 7.5s

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 2.024 sec. / Electron dose: 46 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 42224

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Processing

EM software
IDNameVersionCategory
1RELION4.0.1particle selection
2SerialEMimage acquisition
4CTFFIND4.1CTF correction
7PHENIXmodel fitting
9RELION4.0.1initial Euler assignment
10RELION4.0.1final Euler assignment
11RELION4.0.1classification
12RELION4.0.13D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.42 ° / Axial rise/subunit: 4.76 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 257982
Details: Manual picking followed by particle extraction (box size 900px binned to 300px) resulted in 257982 segments, which were subject to reference-free 2D classification to give 255032 remaining ...Details: Manual picking followed by particle extraction (box size 900px binned to 300px) resulted in 257982 segments, which were subject to reference-free 2D classification to give 255032 remaining segments. These were re-extracted (box size 288px) without binning.
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 12802
Details: 3D auto-refinement was performed using the type I-2 map from the first round of 3D classification low-pass filtered to 10 angstroms, allowing rise and twist parameters to vary. The refined ...Details: 3D auto-refinement was performed using the type I-2 map from the first round of 3D classification low-pass filtered to 10 angstroms, allowing rise and twist parameters to vary. The refined map was subject to standard post-processing in RELION.
Symmetry type: HELICAL
Atomic model buildingProtocol: FLEXIBLE FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0053294
ELECTRON MICROSCOPYf_angle_d0.5374440
ELECTRON MICROSCOPYf_dihedral_angle_d4.407480
ELECTRON MICROSCOPYf_chiral_restr0.05573
ELECTRON MICROSCOPYf_plane_restr0.002558

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