8QZZ
Crystal structure of human eIF2 alpha-gamma complexed with PPP1R15A_420-452
Summary for 8QZZ
| Entry DOI | 10.2210/pdb8qzz/pdb |
| Descriptor | Eukaryotic translation initiation factor 2 subunit 3, Eukaryotic translation initiation factor 2 subunit 1, Protein phosphatase 1 regulatory subunit 15A, ... (4 entities in total) |
| Functional Keywords | eukaryotic initiation factor-2, pp1 regulatory subunit, dephosphorylation, metabolism, translation |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 91549.53 |
| Authors | |
| Primary citation | Yan, Y.,Shetty, M.,Harding, H.P.,George, G.,Zyryanova, A.,Labbe, K.,Mafi, A.,Hao, Q.,Sidrauski, C.,Ron, D. Substrate recruitment via eIF2 gamma enhances catalytic efficiency of a holophosphatase that terminates the integrated stress response. Proc.Natl.Acad.Sci.USA, 121:e2320013121-e2320013121, 2024 Cited by PubMed Abstract: Dephosphorylation of pSer51 of the α subunit of translation initiation factor 2 (eIF2α) terminates signaling in the integrated stress response (ISR). A trimeric mammalian holophosphatase comprised of a protein phosphatase 1 (PP1) catalytic subunit, the conserved C-terminally located ~70 amino acid core of a substrate-specific regulatory subunit (PPP1R15A/GADD34 or PPP1R15B/CReP) and G-actin (an essential cofactor) efficiently dephosphorylate eIF2α in vitro. Unlike their viral or invertebrate counterparts, with whom they share the conserved 70 residue core, the mammalian PPP1R15s are large proteins of more than 600 residues. Genetic and cellular observations point to a functional role for regions outside the conserved core of mammalian PPP1R15A in dephosphorylating its natural substrate, the eIF2 trimer. We have combined deep learning technology, all-atom molecular dynamics simulations, X-ray crystallography, and biochemistry to uncover binding of the γ subunit of eIF2 to a short helical peptide repeated four times in the functionally important N terminus of human PPP1R15A that extends past its conserved core. Binding entails insertion of Phe and Trp residues that project from one face of an α-helix formed by the conserved repeats of PPP1R15A into a hydrophobic groove exposed on the surface of eIF2γ in the eIF2 trimer. Replacing these conserved Phe and Trp residues with Ala compromises PPP1R15A function in cells and in vitro. These findings suggest mechanisms by which contacts between a distant subunit of eIF2 and elements of PPP1R15A distant to the holophosphatase active site contribute to dephosphorylation of eIF2α by the core PPP1R15 holophosphatase and to efficient termination of the ISR in mammals. PubMed: 38547060DOI: 10.1073/pnas.2320013121 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.35 Å) |
Structure validation
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