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- EMDB-53456: Alpha-synuclein K21A fibril type 1A polymorph in the presence of ATP -

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Basic information

Entry
Database: EMDB / ID: EMD-53456
TitleAlpha-synuclein K21A fibril type 1A polymorph in the presence of ATP
Map data
Sample
  • Cell: alpha-Synuclein
    • Protein or peptide: Alpha-synuclein
Keywordsalpha-synuclein / amyloid fibril / type 1A polymorph / protein aggregation / neurodegeneration / Parkinson's disease / ATP binding / ATP hydrolysis / cryo-EM structure / NEUROPEPTIDE
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 / positive regulation of neurotransmitter secretion / SNARE complex assembly / 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 / 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 / inclusion body / axon terminus / 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 speciesEscherichia coli BL21(DE3) (bacteria) / Homo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsFrey L / Riek R / Wittung Stafshede P
Funding support Switzerland, 6 items
OrganizationGrant numberCountry
ETH Zurich Switzerland
Swiss National Science Foundation
Swedish Research Council
The Swedish Cancer Foundation (PWS)
The Synapsis Foundation Switzerland (RR)
Knut and Alice Wallenberg Foundation (PWS)
CitationJournal: Adv Sci (Weinh) / Year: 2025
Title: ATP Hydrolysis by α-Synuclein Amyloids is Mediated by Enclosing β-Strand.
Authors: Lukas Frey / Fiamma Ayelen Buratti / Istvan Horvath / Shraddha Parate / Ranjeet Kumar / Roland Riek / Pernilla Wittung-Stafshede /
Abstract: Pathological amyloids, like those formed by α-synuclein in Parkinson's disease, are recently found to catalyze the hydrolysis of model substrates in vitro. Here it is reported that the universal ...Pathological amyloids, like those formed by α-synuclein in Parkinson's disease, are recently found to catalyze the hydrolysis of model substrates in vitro. Here it is reported that the universal energy molecule ATP is another substrate for α-synuclein amyloid chemical catalysis. To reveal the underlying mechanism, the high-resolution cryo-EM structure of the amyloids in the presence of ATP is solved. The structure reveals a type 1A amyloid fold with an additional β-strand involving residues 16-22 that wraps around the ATP, creating an enclosed cavity at the interface of the protofilaments. Mutations of putative ATP-interacting residues in the cavity and the additional β-strand showed that replacing any one of Lys21, Lys23, Lys43, Lys45, and Lys60 with Ala reduced amyloid-mediated ATPase activity. High-resolution structural analysis of Lys21Ala α-synuclein amyloids in the presence of ATP reveals the same fold as wild-type α-synuclein amyloids but without the extra β-strand and with ATP oriented differently. It is concluded that positively-charged side chains, along with ordering of the N-terminal part into a β-strand, enclosing the cavity, are essential parameters governing ATP hydrolysis by α-synuclein amyloids. Amyloid-catalyzed ATP hydrolysis may hamper ATP-dependent rescue systems near amyloid deposits in vivo.
History
DepositionApr 18, 2025-
Header (metadata) releaseOct 29, 2025-
Map releaseOct 29, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_53456.png

Downloads & links

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Map

FileDownload / File: emd_53456.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 256 pix.
= 332.8 Å		1.3 Å/pix.
x 256 pix.
= 332.8 Å		1.3 Å/pix.
x 256 pix.
= 332.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.3 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.016
Minimum - Maximum-0.051395703 - 0.089074634
Average (Standard dev.)0.000094142866 (±0.0035182962)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 332.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_53456_half_map_1.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Half map: #2

Fileemd_53456_half_map_2.map
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Histogram (log scale)

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Sample components

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Entire : alpha-Synuclein

EntireName: alpha-Synuclein
Components
  • Cell: alpha-Synuclein
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: alpha-Synuclein

SupramoleculeName: alpha-Synuclein / type: cell / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Escherichia coli BL21(DE3) (bacteria)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.418007 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MDVFMKGLSK AKEGVVAAAE ATKQGVAEAA 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: 7.5
Details: 20 mM Tris, 150 mM NaCl, pH 7.5, 1 mM MgCl2, 1 mM ATP
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 288.15 K

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 63.52 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.4 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.63 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 87149
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final angle assignmentType: NOT APPLICABLE

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