Journal
STRUCTURE
Volume 24, Issue 12, Pages 2174-2181Publisher
CELL PRESS
DOI: 10.1016/j.str.2016.09.010
Keywords
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Funding
- NINDS [R01NS091336]
- NIGMS [R01GM098482]
- Fund for Scientific Research-Flanders [G.0473.12, G.0482.12]
- Flemish Concerted Research Action [GOA 15/016]
- US DOE, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- NIH-NIGMS [P41GM103393]
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Specific interactions between proteins govern essential physiological processes including signaling. Many enzymes, especially the family of serine/threonine phosphatases (PSPs: PP1, PP2A, and PP2B/ calcineurin/CN), recruit substrates and regulatory proteins by binding short linear motifs (SLiMs), short sequences found within intrinsically disordered regions that mediate specific protein-protein interactions. While tremendous progress had been made in identifying where and how SLiMs bind PSPs, especially PP1 and CN, essentially nothing is known about how SLiMs bind PP2A, a validated cancer drug target. Here we describe three structures of a PP2A-SLiM interaction (B56:pS-RepoMan, B56:pS-BubR1, and B56: pSpS-BubR1), show that this PP2A-specific SLiM is defined as LSPIxE, and then use these data to discover scores of likely PP2A regulators and substrates. Together, these data provide a powerful approach not only for dissecting PP2A interaction networks in cells but also for targeting PP2A diseases, such as cancer.
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