Regulation of the phosphatase PP2B by protein–protein interactions

Abstract

Protein dephosphorylation is important for regulating cellular signaling in a variety of contexts. Protein phosphatase-2B (PP2B), or calcineurin, is a widely expressed serine/threonine phosphatase that acts on a large cross section of potential protein substrates when activated by increased levels of intracellular calcium in concert with calmodulin. PxIxIT and LxVP targeting motifs are important for maintaining specificity in response to elevated calcium. In the present study, we describe the mechanism of PP2B activation, discuss its targeting by conserved binding motifs and review recent advances in the understanding of an A-kinase anchoring protein 79/PP2B/protein kinase A complex’s role in synaptic long-term depression. Finally, we discuss potential for targeting PP2B anchoring motifs for therapeutic benefit.

Systematic discovery of Short Linear Motifs decodes calcineurin phosphatase signaling

“…Although conserved recognition of PxIxIT and LxVP motifs by CN is well documented (Nygren and Scott, 2016;Roy and Cyert, 2009), challenges inherent to identifying these low affinity and degenerate sequences has limited their discovery. Here, we utilized ProP-PD to triple the number of validated CN-binding motifs in humans and establish a rich collection of PxIxITs and LxVPs that encompass diversity in sequence and binding strength.…”

“…The CN heterodimer, composed of two subunits (catalytic: CNA, regulatory: CNB), recognizes substrates by binding to PxIxIT and LxVP SLiMs ( Figure 1A), a mechanism that is evolutionarily conserved ). However, positioning of these motifs with respect to each other, and to sites of dephosphorylation varies between substrates, and these motifs play distinct roles during dephosphorylation (Nygren and Scott, 2016;Roy and Cyert, 2019). Under non-signaling conditions, the CN heterodimer is inactive due to masking of the active site by autoinhibitory sequences in CNA.…”

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

“…Various small-molecule effectors that modulate (activate or inhibit) protein phosphatase activity and exhibit therapeutic potential for various human diseases have been generated [5,9]. For example, the immunosuppressants cyclosporine A and FK506, which are successfully used to treat acute organ transplant rejection, rheumatoid arthritis, psoriasis and Crohn's disease, target and inhibit protein serine/threonine phosphatase PP2B, also known as PP3 or calcineurin [4,10,11]. Their mode of action, however, was only elucidated after their approval by the US FDA.…”

Intrinsic disorder within AKAP79 fine-tunes anchored phosphatase activity toward substrates and drug sensitivity

“…Additionally, anchored kinases and phosphatases often reside within the same macromolecular complex ( Langeberg and Scott, 2015 ). Such pre-formed bi-directional signaling units modulate key physiological processes including immune responses, glucose homeostasis, renal water balance and excitatory synaptic transmission ( Clipstone and Crabtree, 1992 ; Hinke et al, 2012 ; Nygren and Scott, 2016 ; Sanderson et al, 2012 ; Whiting et al, 2016 ). A unifying molecular principle shared by these wide-ranging physiological responses is that signal termination through targeted phosphatases is the predominant regulatory step.…”