MassIVE MSV000094053

Complete Public PXD049307

Substrate recognition principles for PP2A-B55

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Description

The trimeric PP2A-B55 phosphoprotein phosphatase regulates a plethora of fundamental signaling pathways throughout eukaryotes. How PP2A-B55 selects its substrates presents a severe knowledge gap in our understanding of phospho-dependent signaling. By integrating AlphaFold modelling with comprehensive experimental high-resolution mutational scanning, we show that alpha-helices in interactors bind a conserved platform on the B55 regulatory subunit. Despite limited sequence similarity, these alpha-helices share key amino acid determinants that engage hydrophobic and electrostatic patches on B55 in a remarkably similar way. We characterize a total of 15 instances in yeast, humans, and viruses, suggesting an evolutionarily conserved mechanism. Using this insight and deep learning protein design, we generate a specific and highly potent competitive peptide inhibitor that binds to B55 with low nanomolar affinity. With this inhibitor, we uncover that PP2A-B55 regulates the nuclear exosome targeting (NEXT) complex by binding to an alpha-helical recruitment module in one of its core components, RBM7. Collectively, our findings provide a framework for the understanding and interrogation of PP2A-B55 in health and disease. [doi:10.25345/C5JQ0T58R] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: PP2A-B55 ; B55 ; alpha-helix ; NEXT ; RBM7

Contact

Principal Investigators:
(in alphabetical order) 		Arminja Kettenbach, The Geisel School of Medicine at Dartmouth, United States
Submitting User: madamo
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