Calcineurin

Calcineurin is an enzyme from the group consisting of phosphatases, which plays a key role in the regulation of immune response. It is 2B (gene names starting with PPP3 ) also known as protein phosphatase. Some immunosuppressive drugs such as cyclosporin and tacrolimus exert their effects through the inhibition of calcineurin.

Function

Calcineurin dephosphorylated NF-AT ( nuclear factor of activated T cells), a transcription factor of T lymphocytes, wherein the transcription of various characteristic genes which are responsible, inter alia, for the synthesis of interleukins initiates. Wherein the immune response of activated T lymphocytes is introduced and amplified.

General activation pathway:

Increasing the calcium concentration in the cytosol due to extracellular stimuli, calmodulin is activated by binding of Ca2 . At the calcineurin B subunit meanwhile bind Ca2 ions to the four " EF-hand " - binding motifs. This leads to a conformational change and the autoinhibitory domain of calcineurin A dissolves, the enzyme is partially activated.

Ca2 / calmodulin can now bind to the vacant calmodulin - binding motif of calcineurin A, this causes a further conformational change in the catalytically active form. The holoenzyme is now fully activated. Substrates can now bind to the active calcineurin and dephosphorylated, for example NF-AT or ion antiporter in the membrane of nerve cells.

A second activation mechanism is based on the selective proteolysis of the autoinhibitory domain by calpain. This calcineurin is constitutively activated.

In addition to NF -AT also calcineurin is transported into the nucleus by the current findings, the precise nuclear function of calcineurin is still unclear. The essential meaning for the full transcriptional activity of the calcineurin -NF -AT signaling cascade, however, is undisputed.

Structure

Calcineurin is composed of two subunits, the catalytic subunit of calcineurin A ( 60 kDa) and the regulatory subunit calcineurin B ( about 19 kDa).

Regulatory sub-unit transmits the calcium binding sites, wherein the catalytic subunit of calcineurin, both the B- and the calmodulin - binding sites contributes.

Calcineurin A distinction is made between α, β and γ (Gene PPP3CA, PPP3CB, PPP3CC ), the two isoforms mentioned first ubiquitously, the γ isoform found only in the testis. For calcineurin B are two isoforms of calcineurin B 1 and 2 ( with the genes PPP3R1 and PPP3R2 ).

Pharmacological influence

Some immunosuppressants are used for example in organ transplantation and autoimmune diseases, inhibit the activation of calcineurin. The best-known substances with these effects are cyclosporine and tacrolimus.

Calcineurin and tuberculosis

Calcineurin is also responsible for the expression of coronin 1. This protein is bound by mycobacteria and prevents digestion by cellular lysosomes. Inhibition of calcineurin, such as with cyclosporin, can be suppressed by this mechanism. Herein lies a possible future therapeutic approach against tuberculosis, which was already tested successfully in mice ( Coronin - knockouts and cyclosporine -treated specimens ).