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- EMDB-17693: Cryo EM structure of the type 3C polymorph of alpha-synuclein at ... -

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Basic information

Entry
Database: EMDB / ID: EMD-17693
TitleCryo EM structure of the type 3C polymorph of alpha-synuclein at low pH.
Map data
Sample
  • Complex: alpha-synuclein amyloid fibril
    • Protein or peptide: Alpha-synuclein
Keywordsamyloid / polymorphism / PROTEIN FIBRIL
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / response to desipramine / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / response to desipramine / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / 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 / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of norepinephrine uptake / response to iron(II) ion / negative regulation of dopamine metabolic process / transporter regulator activity / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / negative regulation of microtubule polymerization / synaptic vesicle transport / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / dynein complex binding / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / nuclear outer membrane / cuprous ion binding / positive regulation of exocytosis / response to magnesium ion / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / enzyme inhibitor activity / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / regulation of presynapse assembly / response to type II interferon / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / cellular response to copper ion / 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 / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / excitatory postsynaptic potential / phosphoprotein binding / fatty acid metabolic process / protein tetramerization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / ferrous iron binding / 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 / actin binding / growth cone / cellular response to oxidative stress / cell cortex / neuron apoptotic process / microtubule binding / chemical synaptic transmission / molecular adaptor activity / response to lipopolysaccharide / histone binding / amyloid fibril formation / negative regulation of neuron apoptotic process / mitochondrial outer membrane / lysosome
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsFrey L / Qureshi BM / Kwiatkowski W / Rhyner D / Greenwald J / Riek R
Funding support Switzerland, 2 items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
Other government
Citation
Journal: Elife / Year: 2024
Title: On the pH-dependence of α-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation.
Authors: Lukas Frey / Dhiman Ghosh / Bilal M Qureshi / David Rhyner / Ricardo Guerrero-Ferreira / Aditya Pokharna / Witek Kwiatkowski / Tetiana Serdiuk / Paola Picotti / Roland Riek / Jason Greenwald /
Abstract: The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical ...The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical significance. However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the α-synuclein fibrils hampers efforts in disease-relevant in vitro studies on α-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of α-synuclein fibrils in vitro as a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8-7.4, a pH-dependent selection between Type 1, 2, and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structure in vitro.
#1: Journal: Elife / Year: 2023
Title: On the pH-dependence of alpha-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation
Authors: Frey L / Ghosh D / Qureshi BM / Rhyner D / Pokharna A / Guerrero-Ferreira R / Kwiatkowski W / Serdiuk T / Picotti P / Riek R / Greenwald J
History
DepositionJun 22, 2023-
Header (metadata) releaseMay 29, 2024-
Map releaseMay 29, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17693.png

Downloads & links

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Map

FileDownload / File: emd_17693.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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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.32 Å/pix.
x 256 pix.
= 337.92 Å		1.32 Å/pix.
x 256 pix.
= 337.92 Å		1.32 Å/pix.
x 256 pix.
= 337.92 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.32 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.043612417 - 0.08877264
Average (Standard dev.)0.00024830396 (±0.002500729)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 337.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_17693_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: #1

Fileemd_17693_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : alpha-synuclein amyloid fibril

EntireName: alpha-synuclein amyloid fibril
Components
  • Complex: alpha-synuclein amyloid fibril
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: alpha-synuclein amyloid fibril

SupramoleculeName: alpha-synuclein amyloid fibril / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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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: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
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: 5.8
Component:
ConcentrationFormulaName
10.0 mMPO4phosphate
137.0 mMNaClsodium chloride
2.7 mMKClpotassium chloride
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 3127 / Average exposure time: 1.0 sec. / Average electron dose: 67.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.772 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.995 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0.0) / Number images used: 28022
Startup modelType of model: OTHER
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-8pix:
Cryo EM structure of the type 3C polymorph of alpha-synuclein at low pH.

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