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Publication Abstract from PubMed

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 mouse 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 aII. 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.

Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme.,Fedoryshchak RO, Prechova M, Butler A, Lee R, O'Reilly N, Flynn HR, Snijders AP, Eder N, Ultanir S, Mouilleron S, Treisman R Elife. 2020 Sep 25;9. pii: 61509. doi: 10.7554/eLife.61509. PMID:32975518^[2]

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