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Structure. 2012 Oct 10;20(10):1746-56. doi: 10.1016/j.str.2012.08.003. Epub 2012 Aug 30.

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

Author information

1
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912, USA.

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 α 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 ΦΦ 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.

PMID:
22940584
PMCID:
PMC3472097
DOI:
10.1016/j.str.2012.08.003
[Indexed for MEDLINE]
Free PMC Article

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