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- EMDB-45465: Structure of type I-2 alpha-synuclein filament from multiple syst... -

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Basic information

Entry
Database: EMDB / ID: EMD-45465
TitleStructure of type I-2 alpha-synuclein filament from multiple system atrophy
Map data
Sample
  • Complex: Type I-2 alpha-synuclein filament from multiple system atrophy
    • Protein or peptide: Alpha-synuclein
Keywordsfibril / synuclein / PROTEIN 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 / negative regulation of dopamine metabolic process / positive regulation of neurotransmitter secretion / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / regulation of norepinephrine uptake / negative regulation of microtubule polymerization / regulation of locomotion / synaptic vesicle transport / transporter regulator activity / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / mitochondrial ATP synthesis coupled electron transport / dynein complex binding / positive regulation of receptor recycling / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / enzyme inhibitor activity / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / response to type II interferon / negative regulation of serotonin uptake / 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 / axon terminus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / adult locomotory behavior / 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 / PKR-mediated signaling / protein destabilization / 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 / histone binding / response to lipopolysaccharide / microtubule binding / chemical synaptic transmission / amyloid fibril formation / molecular adaptor activity / 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)
Methodhelical reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYan NL / Candido F / Tse E / Melo AA / Southworth DR / Merz GE
Funding support United States, 3 items
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, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateJan 22, 2025-
Current statusJan 22, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45465.png

Downloads & links

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Map

FileDownload / File: emd_45465.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 288 pix.
= 240.192 Å		0.83 Å/pix.
x 288 pix.
= 240.192 Å		0.83 Å/pix.
x 288 pix.
= 240.192 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0156
Minimum - Maximum-0.04653843 - 0.07844712
Average (Standard dev.)0.00012027504 (±0.0025867394)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 240.192 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_45465_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_45465_half_map_2.map
Projections & Slices
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Sample components

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Entire : Type I-2 alpha-synuclein filament from multiple system atrophy

EntireName: Type I-2 alpha-synuclein filament from multiple system atrophy
Components
  • Complex: Type I-2 alpha-synuclein filament from multiple system atrophy
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Type I-2 alpha-synuclein filament from multiple system atrophy

SupramoleculeName: Type I-2 alpha-synuclein filament from multiple system atrophy
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 18 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum
Molecular weightTheoretical: 14.476108 KDa
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

UniProtKB: Alpha-synuclein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4 / Component - Concentration: 30.0 mM / Component - Name: Tris-HCl
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: Wait time 30s, blot time 7.5s.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 42224 / Average exposure time: 2.024 sec. / Average electron dose: 46.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.76 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.42 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0.1)
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.
Number images used: 12802
Segment selectionNumber selected: 257982 / Software - Name: RELION (ver. 4.0.1)
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.
Startup modelType of model: EMDB MAP
EMDB ID:

10650

Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4.0.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: FLEXIBLE FIT
Output model

PDB-9cda:
Structure of type I-2 alpha-synuclein filament from multiple system atrophy

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