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Discovery of Protein Phosphatase 2A Substrates
Author(s) -
Wang Xinru,
Page Rebecca,
Wolfgang Peti
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.795.2
Subject(s) - protein phosphatase 2 , interactome , phosphatase , computational biology , phosphorylation , serine , calcineurin , biology , threonine , drug discovery , microbiology and biotechnology , biochemistry , chemistry , gene , medicine , surgery , transplantation
The protein ser/thr phosphatases (PSPs) dephosphorylate 1000s of key biological targets, making them attractive therapeutic targets. The serine/threonine protein phosphatases 1 and 2B (PP1; PP2B or calcineurin/CN) bind substrates and regulatory proteins using short functional sequences known as Short Linear Motifs (SLiMs). These SLiMs are found within intrinsically disordered regions (IDRs) of substrates and regulatory proteins and mediate specific protein‐protein interactions. While tremendous progress had been made in identifying where and how SLiMs bind PP1 and CN, very little is known about how substrates are specifically recruited to PP2A, a validated cancer drug target. Here we describe three structures of the first known PP2A‐SLiM interaction (B56:pS‐RepoMan, B56:pS‐BubR1, and B56:pSpS‐BubR1), which reveal that this PP2A‐specific SLiM is defined as LSPIxE. We also show that the affinity of this SLiM for B56 is modulated both by residues immediately adjacent to the SLiM and its phosphorylation, both of which provide the fine‐tuning needed to ensure signaling pathway fidelity. Finally, by using this newly discovered motif, we identify nearly 100 proteins that we predict are novel PP2A:B56 regulators/substrates, substantially expanding the PP2A interactome. We are now leveraging this data to identify new PP2A‐specific SLiMs. Further, we are expanding this approach to discover new SLiMs that are specific for other PSPs, especially PP1 and CN. Together, these data are providing a powerful approach not only for dissecting PSP interaction networks in cells but also for targeting PSP diseases, such as cancer. Support or Funding Information NIH: R01GM098482 NIH: R01NS091336 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .