title: 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 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.
authors.affiliation: Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912, USA.
authors.forename: Nichole
authors.initials: N
authors.lastname: O'Connell
authors.forename: Scott R
authors.initials: SR
authors.lastname: Nichols
authors.forename: Ewald
authors.initials: E
authors.lastname: Heroes
authors.forename: Monique
authors.initials: M
authors.lastname: Beullens
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Peti
authors.forename: Rebecca
authors.initials: R
authors.lastname: Page
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004722:Endoribonucleases / Q000737:chemistry*; D024981:Glycogen Phosphorylase / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010749:Phosphoprotein Phosphatases / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D054645:Protein Phosphatase 1 / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D016601:RNA-Binding Proteins / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D016601:RNA-Binding Proteins; D024981:Glycogen Phosphorylase; D004722:Endoribonucleases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C097081:PPP1R8 protein, human