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- EMDB-16528: 3D reconstruction of alpha-synuclein oligomer-PSMa3 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-16528
Title3D reconstruction of alpha-synuclein oligomer-PSMa3 complex
Map data
Sample
  • Complex: The structural architecture of an alpha-synuclein toxic oligomer with PSMalpha3 peptide
Keywordsalpha-synuclein / oligomers / toxic / symmetric / PSMa3 peptide / NEUROPEPTIDE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 18.3 Å
AuthorsCuellar J / Santos J / Pallares I / Ventura S / Valpuesta JM
Funding support Spain, 1 items
OrganizationGrant numberCountry
Ministerio de Ciencia e Innovacion (MCIN)PID2019-105872GB-I00 Spain
CitationJournal: J Am Chem Soc / Year: 2024
Title: A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.
Authors: Jaime Santos / Jorge Cuellar / Irantzu Pallarès / Emily J Byrd / Alons Lends / Fernando Moro / Muhammed Bilal Abdul-Shukkoor / Jordi Pujols / Lorea Velasco-Carneros / Frank Sobott / Daniel ...Authors: Jaime Santos / Jorge Cuellar / Irantzu Pallarès / Emily J Byrd / Alons Lends / Fernando Moro / Muhammed Bilal Abdul-Shukkoor / Jordi Pujols / Lorea Velasco-Carneros / Frank Sobott / Daniel E Otzen / Antonio N Calabrese / Arturo Muga / Jan Skov Pedersen / Antoine Loquet / Jose María Valpuesta / Sheena E Radford / Salvador Ventura /
Abstract: Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is ...Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.
History
DepositionJan 24, 2023-
Header (metadata) releaseMay 29, 2024-
Map releaseMay 29, 2024-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16528.png

Downloads & links

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Map

FileDownload / File: emd_16528.map.gz / Format: CCP4 / Size: 489.3 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 4.38 Å
Density
Contour LevelBy AUTHOR: 0.054
Minimum - Maximum-0.12492395 - 0.19365734
Average (Standard dev.)0.005384248 (±0.029219761)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions505050
Spacing505050
CellA=B=C: 219.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_16528_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_16528_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The structural architecture of an alpha-synuclein toxic oligomer ...

EntireName: The structural architecture of an alpha-synuclein toxic oligomer with PSMalpha3 peptide
Components
  • Complex: The structural architecture of an alpha-synuclein toxic oligomer with PSMalpha3 peptide

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Supramolecule #1: The structural architecture of an alpha-synuclein toxic oligomer ...

SupramoleculeName: The structural architecture of an alpha-synuclein toxic oligomer with PSMalpha3 peptide
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 420 KDa

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.5 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R2/2 / Material: COPPER/RHODIUM / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 15 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 294 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 852 / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 0.5 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 73000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 187446
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 18.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.0) / Number images used: 26658
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION
Final 3D classificationSoftware - Name: RELION

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