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- EMDB-19443: Alpha-synuclein amyloid fibrils with WT DNAJB1, HSC70, HSP110 and ATP -

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Basic information

Entry
Database: EMDB / ID: EMD-19443
TitleAlpha-synuclein amyloid fibrils with WT DNAJB1, HSC70, HSP110 and ATP
Map dataTomogram of alpha-synuclein amyloid fibrils incubated with WT DNAJB1, Hsc70, Hsp110 and ATP
Sample
  • Complex: Alpha-synuclein amyloid fibrils incubated with WT DNAJB1, HSC70, HSP110 and ATP
KeywordsChaperones / amyloid fibril / disaggregation / PROTEIN FIBRIL
Biological speciesHomo sapiens (human)
Methodelectron tomography / cryo EM
AuthorsSaibil HR / Monistrol J
Funding support United Kingdom, 3 items
OrganizationGrant numberCountry
Wellcome Trust202679/Z/16/Z United Kingdom
Wellcome Trust206166/Z/17/Z United Kingdom
Wellcome Trust106249/Z/14/Z United Kingdom
Citation
Journal: Commun Biol / Year: 2025
Title: Stepwise recruitment of chaperone Hsc70 by DNAJB1 produces ordered arrays primed for bursts of amyloid fibril disassembly.
Authors: Jim Monistrol / Joseph G Beton / Erin C Johnston / Thi Lieu Dang / Bernd Bukau / Helen R Saibil /
Abstract: The Hsp70 chaperone system is capable of disassembling pathological aggregates such as amyloid fibres associated with serious degenerative diseases. Here we examine the role of the J-domain protein ...The Hsp70 chaperone system is capable of disassembling pathological aggregates such as amyloid fibres associated with serious degenerative diseases. Here we examine the role of the J-domain protein co-factor in amyloid disaggregation by the Hsc70 system. We used cryo-EM and tomography to compare the assemblies with wild-type DNAJB1 or inactive mutants. We show that DNAJB1 binds regularly along α-synuclein amyloid fibrils and acts in a 2-step recruitment of Hsc70, releasing DNAJB1 auto-inhibition before activating Hsc70 ATPase. The wild-type DNAJB1:Hsc70:Apg2 complex forms dense arrays of chaperones on the fibrils, with Hsc70 on the outer surface. When the auto-inhibition is removed by mutating DNAJB1 (ΔH5 DNAJB1), Hsc70 is recruited to the fibrils at a similar level, but the ΔH5 DNAJB1:Ηsc70:Apg2 complex is inactive, binds less regularly to the fibrils and lacks the ordered clusters. Therefore, we propose that 2-step activation of DNAJB1 regulates the ordered assembly of Hsc70 on the fibril. The localised, dense packing of chaperones could trigger a cascade of recruitment and activation to give coordinated, sequential binding and disaggregation from an exposed fibril end, as previously observed in AFM videos. This mechanism is likely to be important in maintaining a healthy cellular proteome into old age.
#1: Journal: Biorxiv / Year: 2024
Title: Stepwise recruitment of Hsc70 by DNAJB1 produces ordered arrays primed for bursts of amyloid fibre disassembly
Authors: Monistrol J / Beton JG / Johnston EC / Saibil HR
History
DepositionJan 18, 2024-
Header (metadata) releaseFeb 28, 2024-
Map releaseFeb 28, 2024-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19443.png

Downloads & links

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Map

FileDownload / File: emd_19443.map.gz / Format: CCP4 / Size: 6.9 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTomogram of alpha-synuclein amyloid fibrils incubated with WT DNAJB1, Hsc70, Hsp110 and ATP
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
3.8 Å/pix.
x 466 pix.
= 1770.8 Å		3.8 Å/pix.
x 1951 pix.
= 7413.8 Å		3.8 Å/pix.
x 2033 pix.
= 7725.4 Å

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 3.8 Å
Density

Histogram

Histogram (log scale)
Minimum - Maximum-10390.032999999999447 - 7515.220999999999549
Average (Standard dev.)38.950164999999998 (±473.783450000000016)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin468314
Dimensions19512033466
Spacing20331951466
CellA: 7725.4 Å / B: 7413.8 Å / C: 1770.7999 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Alpha-synuclein amyloid fibrils incubated with WT DNAJB1, HSC70, ...

EntireName: Alpha-synuclein amyloid fibrils incubated with WT DNAJB1, HSC70, HSP110 and ATP
Components
  • Complex: Alpha-synuclein amyloid fibrils incubated with WT DNAJB1, HSC70, HSP110 and ATP

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Supramolecule #1: Alpha-synuclein amyloid fibrils incubated with WT DNAJB1, HSC70, ...

SupramoleculeName: Alpha-synuclein amyloid fibrils incubated with WT DNAJB1, HSC70, HSP110 and ATP
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingelectron tomography
Aggregation statefilament

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Sample preparation

BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMHEPESHEPES
50.0 mMKClPotassium chloride
5.0 mMMgClMagnesium chloride
5.0 mMATPAdenosine triphosphate
2.0 mMDTTDL-1,4-Dithiothreitol
6.0 mMPEPPhosphoenolpyruvate
20.0 ng/uLpyruvate kinase
GridModel: C-flat-1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber temperature: 277.15 K / Instrument: LEICA EM GP
SectioningOther: NO SECTIONING
Fiducial markerManufacturer: EMS / Diameter: 10 nm

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 118.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 6.5 µm / Nominal defocus min: 2.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionSoftware - Name: RELION / Number images used: 121

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