The extended PP1 toolkit: designed to create specificity

Abstract

Protein Ser/Thr phosphatase-1 (PP1) catalyzes the majority of eukaryotic protein dephosphorylation reactions in a highly regulated and selective manner. Recent studies have identified an unusually diversified PP1 interactome with the properties of a regulatory toolkit. PP1-interacting proteins (PIPs) function as targeting subunits, substrates and/or inhibitors. As targeting subunits, PIPs contribute to substrate selection by bringing PP1 into the vicinity of specific substrates and by modulating substrate specificity via additional substrate docking sites or blocking substrate-binding channels. Many of the nearly 200 established mammalian PIPs are predicted to be intrinsically disordered, a property that facilitates their binding to a large surface area of PP1 via multiple docking motifs. These novel insights offer perspectives for the therapeutic targeting of PP1 by interfering with the binding of PIPs or substrates.

Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex

“…PP1 has little innate substrate specificity and requires a substrate targeting subunit to impose specificity and direct it to cellular targets (Bollen et al 2010). We propose that Rif1 represents a previously unidentified PP1 substrate targeting subunit that binds Glc7 and directs it to dephosphorylate Mcm4, thereby countering the action of DDK (Fig.…”

“…HEAT repeats are proposed to form a ''solenoid'' domain functioning in protein-protein interactions (Andrade et al 2001). SILK and RVXF motifs are conserved sequence signatures of Protein Phosphatase 1 (PP1)-interacting proteins that mediate binding to PP1 (Bollen et al 2010). Consistent with the presence of PP1 interaction motifs, Rif1 was reported to interact physically with PP1 in budding yeast (Breitkreutz et al 2010), but the physiological significance of PP1-Rif1 interaction has been unclear.…”

“…PP1 targeting proteins are diverse, generally showing no sequence similarity beyond the presence of at least one PP1 interaction (e.g., RVXF or SILK) motif (Wakula et al 2003). These PP1 interaction motifs are also found in other PP1-interacting proteins, including PP1 substrates and inhibitory regulators (Bollen et al 2010). For all such PP1-interacting proteins, physical interaction via PP1 interaction motifs is important for them to direct PP1 function in vivo.…”

Temperature-sensitive ipl1-2/Aurora B mutation is suppressed by mutations in TOR complex 1 via the Glc7/PP1 phosphatase

“…PP1 is regulated by its interaction with a diverse group of PP1-binding proteins that target PP1 to specific subcellular locations, activate the catalytic subunit toward specific substrates, or inhibit its activity (18). Although two mammalian kinetochore proteins, KNL1 (19) and CENP-E (20), have recently been shown to have PP1-binding sites that are required for proper kinetochore function, the nature of the PP1/Glc7 activity that opposes Ipl1 in yeast is unclear.…”

The Biochemistry of Mitosis

“…As discussed above, in large part, the catalytic subunit of PP1 is regulated by recruiting it to specific proteins at precise times. These proteins have docking sites for PP1 with a core consensus motif of (R/K-V-X-F), (F-x-x-R/K-x-R/K), or (RRVTW) (Bollen et al 2010;Heroes et al 2013). In addition, there is a global inhibition of PP1 activity as cells enter mitosis because cyclin B -Cdk phosphorylates the catalytic subunit of PP1 at an inhibitory site on its carboxyl terminus ).…”