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Publication Abstract from PubMed

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 2alpha (eIF2alpha). G-actin, whose essential role in eIF2alpha dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2alpha to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2alpha kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR.

Higher-order phosphatase-substrate contacts terminate the integrated stress response.,Yan Y, Harding HP, Ron D Nat Struct Mol Biol. 2021 Oct;28(10):835-846. doi: 10.1038/s41594-021-00666-7. , Epub 2021 Oct 8. PMID:34625748^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.