The molecular basis for substrate specificity of the nuclear NIPP1:PP1 holoenzyme.

ABSTRACT: 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 ? 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 ?? 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.

SUBMITTER: O'Connell N 

PROVIDER: S-EPMC3472097 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature