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- EMDB-50860: Cryo EM map of the type 2A polymorph of alpha-synuclein at pH 7.0. -

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Basic information

Entry
Database: EMDB / ID: EMD-50860
TitleCryo EM map of the type 2A polymorph of alpha-synuclein at pH 7.0.
Map data
Sample
  • Complex: alpha-synuclein amyloid fibril
    • Protein or peptide: alpha-synuclein
Keywordsamyloid / polymorphism / PROTEIN FIBRIL
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.86 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: 2024
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 / Guerrero-Ferreira R / Pokharna A / Kwiatkowski W / Serdiuk T / Picotti P / Riek R / Greenwald J
History
DepositionJul 3, 2024-
SupersessionJul 17, 2024ID: EMD-50076
Header (metadata) releaseJul 17, 2024-
Map releaseJul 17, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50860.png

Downloads & links

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Map

FileDownload / File: emd_50860.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.88 Å/pix.
x 128 pix.
= 240.64 Å		1.88 Å/pix.
x 128 pix.
= 240.64 Å		1.88 Å/pix.
x 128 pix.
= 240.64 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel size
XYZ
EMDB info.1.31.31.3
CCP4 map header1.881.881.88
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.089811124 - 0.18602459
Average (Standard dev.)0.00075981213 (±0.008253986)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 260.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_50860_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFMKGLSK AKEGVVAAA E KTKQGVAE AA GKTKEGV LYV GSKTKE GVVH GVATV AEKTK EQVT NVGGAV VTG VTAVAQK TV EGAGSIAA A TGFVKKDQL GKNEEGAPQE GILEDMPVD P DNEAYEMP SE EGYQDYE PEA

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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
Component:
ConcentrationFormulaName
10.0 mMPO4Phosphate
137.0 mMNaClSodium Chloride
2.7 mMKClPotassiu 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: 1339 / Average exposure time: 1.0 sec. / Average electron dose: 58.5 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: 4.82 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.80 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0.0) / Number images used: 91238
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

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