Substrate and phosphorylation site selection by phosphoprotein phosphatases

Global mass spectrometry-based phosphoproteomic analyses have revealed preferences of phosphoprotein phosphatases (PPPs) for distinct phosphorylation site consensus motifs. Phosphoacceptor and phosphorylation site preferences determine dephosphorylation kinetics and provide temporal control of signaling events. Identification of a growing number of PPP holoenzyme-specific short linear motifs (SLiMs) has revealed specific PPP–substrate/scaffold interactions. SLiM-containing proteins are direct PPP substrates or function as scaffolds for indirect substrate recruitment. Phosphorylation site preferences, SLiM affinity, and distance between the phosphorylation site and SLiM combinatorially contribute to the dephosphorylation kinetics. Recent studies demonstrated PPP phosphorylation site preferences and modulation of SLiM affinity in biological contexts, specifically mitosis. Dynamic protein phosphorylation and dephosphorylation are essential regulatory mechanisms that ensure proper cellular signaling and biological functions. Deregulation of either reaction has been implicated in several human diseases. Here, we focus on the mechanisms that govern the specificity of the dephosphorylation reaction. Most cellular serine/threonine dephosphorylation is catalyzed by 13 highly conserved phosphoprotein phosphatase (PPP) catalytic subunits, which form hundreds of holoenzymes by binding to regulatory and scaffolding subunits. PPP holoenzymes recognize phosphorylation site consensus motifs and interact with short linear motifs (SLiMs) or structural elements distal to the phosphorylation site. We review recent advances in understanding the mechanisms of PPP site-specific dephosphorylation preference and substrate recruitment and highlight examples of their interplay in the regulation of cell division. Dynamic protein phosphorylation and dephosphorylation are essential regulatory mechanisms that ensure proper cellular signaling and biological functions. Deregulation of either reaction has been implicated in several human diseases. Here, we focus on the mechanisms that govern the specificity of the dephosphorylation reaction. Most cellular serine/threonine dephosphorylation is catalyzed by 13 highly conserved phosphoprotein phosphatase (PPP) catalytic subunits, which form hundreds of holoenzymes by binding to regulatory and scaffolding subunits. PPP holoenzymes recognize phosphorylation site consensus motifs and interact with short linear motifs (SLiMs) or structural elements distal to the phosphorylation site. We review recent advances in understanding the mechanisms of PPP site-specific dephosphorylation preference and substrate recruitment and highlight examples of their interplay in the regulation of cell division. a region of a chromosome where sister chromatids are held together and the kinetochore assembles. a process of aligning chromosomes on the metaphase plate. a biochemically active enzyme complex formed by a combination of an enzyme and its coenzyme. a stretch of amino acids in a protein not likely to support the formation of three-dimensional folded structures. a large protein complex that assembles on the centromere and is the attachment site for spindle microtubules. a stretch of four to ten amino acids with three to five residues that mediate protein–protein interactions. SLiMs are degenerate in sequence and often located in intrinsically disordered regions of the protein.