9NB9
Viral protein DP71L in complex with phosphorylated eIF2alpha (NTD) and protein phosphatase 1A (D64A), stabilized by G-actin/DNAseI
Summary for 9NB9
| Entry DOI | 10.2210/pdb9nb9/pdb |
| EMDB information | 49223 |
| Descriptor | Protein DP71L, Serine/threonine-protein phosphatase PP1-alpha catalytic subunit, Actin, alpha skeletal muscle, ... (8 entities in total) |
| Functional Keywords | phosphatase, complex, isr, translation |
| Biological source | African swine fever virus More |
| Total number of polymer chains | 5 |
| Total formula weight | 141841.22 |
| Authors | Reineke, L.C.,Dalwadi, U.,Croll, T.,Arthur, C.,Lee, D.J.,Frost, A.,Costa-Mattioli, M. (deposition date: 2025-02-13, release date: 2025-07-09) |
| Primary citation | Reineke, L.C.,Zhu, P.J.,Dalwadi, U.,Dooling, S.W.,Liu, Y.,Wang, I.C.,Young-Baird, S.,Okoh, J.,Kuncha, S.K.,Zhou, H.,Kannan, A.,Park, H.,Debeaubien, N.A.,Croll, T.,Lee, D.J.,Arthur, C.,Dever, T.E.,Walter, P.,Chen, J.,Frost, A.,Costa-Mattioli, M. Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction. Biorxiv, 2025 Cited by PubMed 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 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. PubMed: 40568171DOI: 10.1101/2025.02.28.640897 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.03 Å) |
Structure validation
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