Calcineurin

Myristic acid may be linked via an amide bond to the a-amino group of the N-terminal glycine residue of selected proteins (Figure 9.18). The reaction is referred to as A -myristoylation and is catalyzed by myristoyl—CoAtprolein N-myris-toyltransferase, known simply as NMT. A -Myristoyl-anchored proteins include the catalytic subunit of cAMP-dependent protein kinase, the ppSff tyrosine kinase, the phosphatase known as calcineurin B, the a-subunit of G proteins (involved in GTP-dependent transmembrane signaling events), and the gag proteins of certain retroviruses, including the FHV-l virus that causes AIDS. 

Calcineurin homologous protein (CHP) is ubiquitously expressed and has four EF-hand domains and one putative site of myristoylation. 

Calmyrin is closely related to human calcineurin B. Calmyrin interacts with presenilin 2 and may thus be involved in Alzheimer s disease. 

Calcineurin is involved in cardiac hypertrophy and in cognitive and behavioral defects in the brain. Inhibitors of calcineurin such as cyclosporine A and FK 506 are used clinically in transplant rejection and autoimmune diseases. 

A secondary metabolite produced by Tolypocladium inflation. This fungus was initially isolated in a soil sample collected in Norway. Cyclosporin A is a cyclic undecapeptide. Inside cells, cyclosporine A binds its immunophillin receptor known as cyclophillin. Like the FK506-FKBP12 complex, cyclosporin A-cyclophillin binds and inhibits the protein phosphatase calcineurin. 

FKBP12 is a member of immunophilin family that has prolyl isomerase activity and is related to the cyclophi-lins in function. FKBP12 binds immunosuppressant molecule FK506 (tacrolimus). The FBKP-FK506 complex inhibits calcineurin, a protein phosphatase, thus blocking signal transduction in the T-lymphocyte... 

Cyclosporine A (CsA) is a water-insoluble cyclic peptide from a fungus composed of 11 amino acids. CsA binds to its cytosolic receptor cyclophilin. The CsA/cyclophilin complex reduces the activity of the protein phosphatase calcineurin. Inhibition of this enzyme activity interrupts antigen receptor-induced activation and translocation of the transcription factor NEAT to the nucleus which is essential for the induction of cytokine synthesis in T-lymphocytes. 

Tacrolimus (TRL), in the past also named FK506, belongs to the group of macrolides and is produced by a special actinomycete species. TRL binds to its cytosolic receptor FKBP-12, however, it also blocks calcineurin activity and subsequently cytokine synthesis. 

The NHR contains also the conserved Calcineurin docking site, PxlxIT, required for the physical interaction of NEAT and Calcineurin. Dephosphorylation of at least 13 serines residues in the NHR induces a conformational change that exposes the nuclear localization sequences (NLS), allowing the nuclear translocation of NEAT. Rephosphorylation of these residues unmasks the nuclear export sequences that direct transport back to the cytoplasm. Engagement of receptors such as the antigen receptors in T and B cells is coupled to phospholipase C activation and subsequent production of inositol triphosphate. Increased levels of inositol triphosphate lead to the initial release of intracellular stores of calcium. This early increase of calcium induces opening of the plasma membrane calcium-released-activated-calcium (CRAC) channels,... 

Hogan PG, Chen L, Nardone J et al (2003) Transcriptional regulation by calcium, calcineurin, and NFAT Genes Dev 17 2205-2232... 

TPR) domains. PP2B (calcineurin) is a heterodimer of a catalytic A-subunit together with a regulatory, Ca2+-binding B-subunit. The A-subunit additionally carries a calmodulin binding site and an autoinhibitory domain. PP7 also contains EF-hand motifs. Both, PP2B and PP7 are stimulated by Ca2+-ions. 

Rapamycin has been known for many years to possess immunosuppressive activity by interfering with the activation of B- and T-cells by interleukin-2. Indeed the first clinically approved indication for rapamycin was renal transplantation. Currently, rapamycin and RAD001 also show promise in liver transplantation and cardiac transplantation, respectively. Generally, treatment protocols utilize a combination of an mTORCl inhibitor, a calcineurin inhibitor and steroids to optimize immunosuppression and minimize nephrotoxicity and other side effects. Rapalogs are also... 

A number of additional proteins play various roles in the structure and function of muscle. They include titin (the largest protein known), nebufin, a-actinin, desmin, dystrophin, and calcineurin. Some properties of these proteins are summarized in Table 49-2. 

Calcineurin Cytosol A calmodulin-regulated protein phosphatase. May play important roles in cardiac hypertrophy and in regulating amounts of slow and fast twitch muscles. 

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