Journal
STRUCTURE
Volume 20, Issue 10, Pages 1746-1756Publisher
CELL PRESS
DOI: 10.1016/j.str.2012.08.003
Keywords
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Funding
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886]
- National Institute of Neurological Disorders and Stroke [R01NS056128]
- National Institute of General Medicine [R01GM098482]
- American Cancer Society [RSG-08-067-01-LIB]
- Fund for Scientific Research-Flanders [G.0478.08]
- Flemish Concerted Research Action [GOA 10/16]
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Regulation of protein phosphatase 1 (PP1) is controlled by a diverse array of regulatory proteins. However, how these proteins direct PP1 specificity is not well understood. More than one-third of the nuclear pool of PP1 forms a holoenzyme with the nuclear inhibitor of PP1, NIPP1, to regulate chromatin remodeling, among other essential biological functions. Here, we show that the PP1-binding domain of NIPP1 is an intrinsically disordered protein, which binds PP1 in an unexpected manner. NIPP1 forms an alpha helix that engages PP1 at a unique interaction site, using polar rather than hydrophobic contacts. Importantly, the structure also reveals a shared PP1 interaction site outside of the RVxF motif, the Phi Phi motif. Finally, we show that NIPP1:PP1 substrate selectivity is determined by altered electrostatics and enhanced substrate localization. Together, our results provide the molecular basis by which NIPP1 directs PP1 substrate specificity in the nucleus.
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