Journal
MOLECULAR CELL
Volume 63, Issue 4, Pages 686-695Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.06.024
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Funding
- Novo Nordisk Foundation [NNF14CC0001]
- Danish Cancer Society
- Novo Nordisk Foundation Center for Protein Research [PI Guillermo Montoya, PI Jakob Nilsson, PI Jesper Velgaard Olsen] Funding Source: researchfish
- The Danish Cancer Society [R124-A7827, R124-A7657, R72-A4351] Funding Source: researchfish
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Dynamic protein phosphorylation is a fundamental mechanism regulating biological processes in all organisms. Protein phosphatase 2A (PP2A) is the main source of phosphatase activity in the cell, but the molecular details of substrate recognition are unknown. Here, we report that a conserved surface-exposed pocket on PP2A regulatory B56 subunits binds to a consensus sequence on interacting proteins, which we term the LxxIxE motif. The composition of the motif modulates the affinity for B56, which in turn determines the phosphorylation status of associated substrates. Phosphorylation of amino acid residues within the motif increases B56 binding, allowing integration of kinase and phosphatase activity. We identify conserved LxxIxE motifs in essential proteins throughout the eukaryotic domain of life and in human viruses, suggesting that the motifs are required for basic cellular function. Our study provides a molecular description of PP2A binding specificity with broad implications for understanding signaling in eukaryotes.
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