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Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme

By Roman O. Fedoryshchak, Magdalena Přechová, Abbey Butler, Rebecca Lee, Nicola O’Reilly, Helen Flynn, Ambrosius P. Snijders, Noreen Eder, Sila Ultanir, Stéphane Mouilleron, Richard Treisman

Posted 28 Jun 2020
bioRxiv DOI: 10.1101/2020.06.28.176040

PPP-family phosphatases such as PP1 have little intrinsic specificity. Cofactors can target PP1 to substrates or subcellular locations, but it remains unclear how they might confer sequence-specificity on PP1. The cytoskeletal regulator Phactr1 is a neuronally-enriched PP1 cofactor that is controlled by G-actin. Structural analysis showed that Phactr1 binding remodels PP1's hydrophobic groove, creating a new composite surface adjacent to the catalytic site. Using phosphoproteomics, we identified numerous fibroblast and neuronal Phactr1/PP1 substrates, which include cytoskeletal components and regulators. We determined high-resolution structures of Phactr1/PP1 bound to the dephosphorylated forms of its substrates IRSp53 and spectrin αII. Inversion of the phosphate in these holoenzyme-product complexes supports the proposed PPP-family catalytic mechanism. Substrate sequences C-terminal to the dephosphorylation site make intimate contacts with the composite Phactr1/PP1 surface, which are required for efficient dephosphorylation. Sequence specificity explains why Phactr1/PP1 exhibits orders-of-magnitude enhanced reactivity towards its substrates, compared to apo-PP1 or other PP1 holoenzymes. ### Competing Interest Statement The authors have declared no competing interest.

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