Emerging insights into serine/threonine-specific phosphoprotein phosphatase function and selectivity

Abstract

Protein phosphorylation on serine and threonine residues is a widely distributed post-translational modification on proteins that acts to regulate their function. Phosphoprotein phosphatases (PPPs) contribute significantly to a plethora of cellular functions through the accurate dephosphorylation of phosphorylated residues. Most PPPs accomplish their purpose through the formation of complex holoenzymes composed of a catalytic subunit with various regulatory subunits. PPP holoenzymes then bind and dephosphorylate substrates in a highly specific manner. Despite the high prevalence of PPPs and their important role for cellular function, their mechanisms of action in the cell are still not well understood. Nevertheless, substantial experimental advancements in (phospho-)proteomics, structural and computational biology have contributed significantly to a better understanding of PPP biology in recent years. This Review focuses on recent approaches and provides an overview of substantial new insights into the complex mechanism of PPP holoenzyme regulation and substrate selectivity.

Phosphatase specificity principles uncovered by MRBLE:Dephos and global substrate identification

“…PP1 and PP2A are members of the phosphoprotein phosphatase (PPP) family and are responsible for the majority of Ser/Thr dephosphorylation in eukaryotes (Shi, 2009; Nilsson, 2019; Kokot & Kohn, 2022). PP1 is an evolutionarily conserved phosphatase with three nearly identical isoforms of the catalytic subunit (PP1Cα‐γ) (Bollen et al , 2010; Heroes et al , 2013).…”

An uncommon phosphorylation mode regulates the activity and protein-interactions of N-acetylglucosamine kinase

“…To maintain dynamic control over protein function, phosphorylation of proteins is typically reversible, and dephosphorylation is catalyzed by protein phosphatases. [44][45] Phosphatases that would remove one or two phosphoryl groups from pyrophosphoproteins have not been described to date. To investigate possible dephosphorylation reactions, we prepared cell lysates from HEK293T cells, and first monitored the dephosphorylation of pS76-NAGK by Q-TOF-MS (Figure 5a).…”

PSL Chemical Biology Symposia Third Edition: A Branch of Science in its Explosive Phase

“…She presented her laboratory's approach to activate specifically a serine/threonine‐specific protein phosphatase, responsible for the majority of the dephosphorylation reactions, with a synthetic peptide. Protein phosphatase‐1 (PP1) and 2A (PP2A) work on specific substrates during many cellular processes and are regulated by diverse holoenzymes, whose dysregulation contributes to diseases such as cancer, diabetes, and heart failure [33] . Her approach to control this protein‐protein interaction is different from the common small‐molecule pan‐inhibitor as it involves highly specific, optimized, and cell‐permeable PP1‐disrupting peptides (PDPs), which disinhibit PP1 in cells [34] .…”

“…Protein phosphatase-1 (PP1) and 2A (PP2A) work on specific substrates during many cellular processes and are regulated by diverse holoenzymes, whose dysregulation contributes to diseases such as cancer, diabetes, and heart failure. [33] Her approach to control this protein-protein interaction is different from the common small-molecule pan-inhibitor as it involves highly specific, optimized, and cell-permeable PP1-disrupting peptides (PDPs), which disinhibit PP1 in cells. [34] They then studied whether this mechanism of action could help rescue the sarcoplasmic reticulum (SR) calcium leak in human patient tissues suffering from cardiomyopathy or cardiac hypertrophy.…”