Interaction of calcineurin with substrates and targeting proteins

Abstract

Calcineurin is a calcium-activated protein phosphatase with a major role in calcium signaling in diverse cells and organs, and importance in clinical practice as the target of the immunosuppressive drugs cyclosporin A and FK506. Cell biological studies have focused mainlyy on the role of calcineurin in transcriptional signaling. Calcium entry in response to extracellular stimuli results in calcineurin activation and signal transmission from the cytosol into the nucleus through dephosphorylation and nuclear translocation of the transcription factor NFAT. This initiates a cascade of transcriptional events involved in physiological and developmental processes. Molecular analyses of the calcineurin/NFAT interaction have been extended recently to encompass the interaction of calcineurin with other substrates, targeting proteins and regulators of calcineurin activity. These studies have increased our understanding of how this essential calciumactivated enzyme orchestrates intracellular events in cooperation with other signaling pathways, and suggested a link between altered calcineurin signaling and the developmental anomalies of Down syndrome.

Cooperative autoinhibition and multi-level activation mechanisms of calcineurin

“…The substrates and regulators of CN contain at least one of the two conserved CN-binding motifs, PxIxIT and LxVP, which interact with two distinct docking sites on CN [3,[20][21][22][23]. Recently, Grigoriu et al [24] reported the first high-resolution structure of CN α bound to a physiological binding partner, the protein inhibitor A238L from African swine fever virus.…”

“…Calcineurin (CN), also known as protein phosphatase 2B (PP2B), is the only known protein Ser/Thr phosphatase directly regulated by calcium and calmodulin (CaM) [1][2][3]. Coupling Ca 2+ signals to cellular responses, CN has diverse biological functions and plays a critical role in many physiological processes, including the immune response, apoptosis, muscle differentiation, bone formation, and neuronal signaling.…”

“…It contains four Ca 2+ -binding loops and is tightly bound to CNA-BBH. A widely accepted model for CN activation involves sequential changes in CN conformation [3,12]. At low Ca 2+ concentrations, CN exists in an inactive state in which only two high-affinity binding sites on CNB are occupied by Ca 2+ .…”

The Calcium/Calcineurin Pathway Promotes Hemidesmosome Stability through Inhibition of β4 Integrin Phosphorylation

“…Because reversible protein phosphorylation catalyzed by protein kinases and protein phosphatases regulates numerous cellular processes including ␤4 function, we sought to determine the role of phosphatases in Ser 1356 phosphorylation. The serine-threonine protein phosphatase calcineurin (CN, also known as protein phosphatase 2b) is known to play an important role in the dephosphorylation of a significant number of proteins and regulates a variety of signaling networks (25,30). CN is regulated by Ca 2ϩ through calmodulin, and it is inhibited by immunosuppressive drugs such as CsA and Tacrolimus (FK506) (25).…”

The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation

“…Calcineurin (Cn) is a calcium/calmodulin-dependent serine/threonine phosphatase composed of two subunits: a catalytic A subunit (CnA) and a regulatory B subunit (CnB) (Li H et al, 2011). Activation of CnA catalytic activity is mediated by CnB and calmodulin in response to an increase in intracellular calcium.…”