7NZM
Cryo-EM structure of pre-dephosphorylation complex of phosphorylated eIF2alpha with trapped holophosphatase (PP1A_D64A/PPP1R15A/G-actin/DNase I)
Summary for 7NZM
| Entry DOI | 10.2210/pdb7nzm/pdb |
| EMDB information | 12665 |
| Descriptor | Eukaryotic translation initiation factor 2 subunit 1, Serine/threonine-protein phosphatase PP1-alpha catalytic subunit, Actin, alpha skeletal muscle, intermediate form, ... (8 entities in total) |
| Functional Keywords | holophosphatase, pp1, ppp1r15a, phosphorylated eif2alpha, hydrolase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 176576.99 |
| Authors | Yan, Y.,Hardwick, S.,Ron, D. (deposition date: 2021-03-24, release date: 2021-09-29, Last modification date: 2024-10-23) |
| Primary citation | Yan, Y.,Harding, H.P.,Ron, D. Higher-order phosphatase-substrate contacts terminate the integrated stress response. Nat.Struct.Mol.Biol., 28:835-846, 2021 Cited by PubMed Abstract: Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c-PPP1R15A-G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin, whose essential role in eIF2α dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2α to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR. PubMed: 34625748DOI: 10.1038/s41594-021-00666-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.96 Å) |
Structure validation
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