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- EMDB-49163: Focused refinement of the Dp71L-eIF2alpha-PP1A subcomplex within ... -

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Basic information

Entry
Database: EMDB / ID: EMD-49163
TitleFocused refinement of the Dp71L-eIF2alpha-PP1A subcomplex within the holo-phosphatase complex.
Map data
Sample
  • Complex: PP1A holo-phosphatase complex with DP71L, G-actin, DNAseI, and substrate phospho-eIF2alpha
KeywordsComplex / Phosphatase / Viral / VIRAL PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsDalwadi U / Reineke LC / Lee DJ / Arthur C / Croll T / 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 10, 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_49163.png

Downloads & links

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Map

FileDownload / File: emd_49163.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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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: 0.029
Minimum - Maximum-0.18870899 - 0.2600953
Average (Standard dev.)0.00041706298 (±0.0021779626)
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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Mask #1

Fileemd_49163_msk_1.map
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AxesZYX

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Half map: #2

Fileemd_49163_half_map_1.map
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Half map: #1

Fileemd_49163_half_map_2.map
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Sample components

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Entire : PP1A holo-phosphatase complex with DP71L, G-actin, DNAseI, and su...

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

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Supramolecule #1: PP1A holo-phosphatase complex with DP71L, G-actin, DNAseI, and su...

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

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / 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 / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 309745
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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