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- EMDB-49124: Consensus reconstruction of the Dp71L-PP1A-eIF2alpha holophosphat... -

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Basic information

Entry
Database: EMDB / ID: EMD-49124
TitleConsensus reconstruction of the Dp71L-PP1A-eIF2alpha holophosphatase stabilized by G-actin/DNAseI
Map data
Sample
  • Complex: PP1A holo-phosphatase complex with viral protein DP71L, G-actin, DNAseI, and substrate phospho-eIF2alpha
KeywordsPhosphatase / complex / ISR / TRANSLATION
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsReineke LC / Dalwadi U / Croll T / Arthur C / Lee DJ / Frost A / Costa-Mattioli M
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: bioRxiv / Year: 2025
Title: Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction.
Abstract: The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts ...The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15B genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B•PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions-including Down syndrome, Alzheimer's disease and aging-but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies.
History
DepositionFeb 7, 2025-
Header (metadata) releaseJul 9, 2025-
Map releaseJul 9, 2025-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49124.png

Downloads & links

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Map

FileDownload / File: emd_49124.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 320 pix.
= 297.152 Å		0.93 Å/pix.
x 320 pix.
= 297.152 Å		0.93 Å/pix.
x 320 pix.
= 297.152 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9286 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0275
Minimum - Maximum-0.047511872 - 0.11990514
Average (Standard dev.)0.00041689456 (±0.002514175)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 297.152 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_49124_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_49124_half_map_2.map
Projections & Slices
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Histogram

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Sample components

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Entire : PP1A holo-phosphatase complex with viral protein DP71L, G-actin, ...

EntireName: PP1A holo-phosphatase complex with viral protein DP71L, G-actin, DNAseI, and substrate phospho-eIF2alpha
Components
  • Complex: PP1A holo-phosphatase complex with viral protein DP71L, G-actin, DNAseI, and substrate phospho-eIF2alpha

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Supramolecule #1: PP1A holo-phosphatase complex with viral protein DP71L, G-actin, ...

SupramoleculeName: PP1A holo-phosphatase complex with viral protein DP71L, G-actin, DNAseI, and substrate phospho-eIF2alpha
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 140 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

Concentration5.5 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
150.0 mMKClPotassium chloride
1.0 mMMnCl2Manganese chloride
0.2 mMATPAdenosine triphosphate
0.2 mMTCEPtris(2-carboxyethyl)phosphine
1.0 mMCaCl2Calcium chloride
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 25
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV / Details: 3.5 uL volume, -5 blot force, 1.5 blot time.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 5236 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 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

Particle selectionNumber selected: 1315944
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.0) / Number images used: 309745
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 80 / Avg.num./class: 7290
Details: A final 2D classification was carried out to exclude poorly aligning or noisy particles.
FSC plot (resolution estimation)

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