Calcineurin

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Calcineurin
Calcineurin
Ribbon model of the heterodimer Aα + B1 (from above / frontal) according to PDB  1AUI
Mass / length primary structure approx. 690 = approx. 520 + 170 amino acids
Secondary to quaternary structure A + B (α / β / γ + 1/2)
Cofactor Fe 3+ , Zn 2+ , calmodulin (A); 4 Ca 2+  (B)
Isoforms 3 * 2
Identifier
Gene name (s) PPP3CA , PPP3CB , PPP3CC , PPP3R1 , PPP3R2
Enzyme classification
EC, category 3.1.3.16 ,  phosphatase
Response type Dephosphorylation
Substrate Serine / threonine phosphate + H 2 O
Products Serine / threonine + phosphate

Calcineurin is an enzyme from the phosphatase group which activates the transcription factor NF-AT ( nuclear factor of activated T cells ) and thus plays a key role in regulating the immune response . It is also known as protein phosphatase 2B ( gene names beginning with PPP3 ). Some immunosuppressive drugs, such as ciclosporin and tacrolimus , work by blocking calcineurin.

function

Calcineurin dephosphorylates the nuclear localization signal of the transcription factor NF-AT . This allows NF-AT to be transported into the nucleus and become active as a transcription factor. NF-AT is mainly active in T lymphocytes , where it regulates the transcription of various characteristic genes , which are responsible for the synthesis of interleukins , among other things , during T cell activation . This initiates and strengthens the immune response of the activated T lymphocytes.

In addition to NF-AT, according to current knowledge, calcineurin is also transported into the cell nucleus , although the exact nuclear function of calcineurin is still unclear. The essential importance for the full transcriptional activity of the calcineurin NF-AT signal cascade is, however, undisputed.

structure

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

The regulatory subunit B has four EF hand binding motifs for calcium ions, while the catalytic subunit A has binding sites for calcineurin B and for the regulatory protein calmodulin .

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

activation

Calcineurin is activated by the influx of calcium into the cell and the calcium-binding regulatory protein calmodulin . If the calcium concentration in the cytosol increases due to extracellular stimuli, calmodulin is activated by binding Ca 2+ . The increased calcium concentration also leads to the binding of Ca 2+ ions to the four “EF-hand” binding motifs of the calcineurin B subunit. This leads to a conformational change of calcineurin and the autoinhibitory domain of calcineurin A dissolves. In this state the enzyme is partially activated. Ca 2+ / calmodulin can now bind to the released calmodulin binding motif of calcineurin A, which causes a further change in conformation to the catalytically active form. The holoenzyme is now fully activated. Substrates can now bind to the active calcineurin and be dephosphorylated, for example NF-AT or ion antiporters in the membrane of nerve cells.

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

Pharmacological influence

Some immunosuppressants , such as those used in organ transplants and autoimmune diseases , inhibit the activation of calcineurin. The best-known substances with this effect are ciclosporin 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 the cellular lysosomes . By inhibiting calcineurin, e.g. B. with ciclosporin, this mechanism can be suppressed. This is a possible future therapeutic approach against tuberculosis , which has already been successfully tested on mice (coronin knockouts and ciclosporin treated specimens).

Calcineurin and male contraception

Recent Japanese research is raising hopes that inhibiting the γ-isoform of calcineurin, which occurs only in the testes, robs male sperm of the ability to fertilize and thus opens up new possibilities in male contraception.

literature

  • GR Crabtree : Generic signals and specific outcomes: signaling through Ca2 +, calcineurin, and NF-AT. In Cell . 1999 Mar 5; 96 (5): 611-4. PMID 10089876

Individual evidence

  1. ↑ LT Kakalis, M. Kennedy et al. a .: Characterization of the calcium-binding sites of calcineurin B. In: FEBS Letters Volume 362, number 1, March 1995, pp. 55-58. PMID 7698353 .
  2. ^ F. Rusnak, P. Mertz: Calcineurin: form and function. In: Physiological reviews Volume 80, Number 4, October 2000, pp. 1483-1521. PMID 11015619 . (Review).
  3. ↑ CB Klee, H. Ren, X. Wang : Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. In: The Journal of biological chemistry Volume 273, Number 22, May 1998, pp. 13367-13370. PMID 9593662 . (Review).
  4. ↑ H. Li, A. Rao, PG Hogan: Interaction of calcineurin with substrates and targeting proteins. In: Trends in cell biology Volume 21, Number 2, February 2011, pp. 91-103. doi : 10.1016 / j.tcb.2010.09.011 . PMID 21115349 . (Review).
  5. ↑ Haruhiko Miyata, Yuhkoh Satouh, u. a .: Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive , Science, October 23, 2015, Vol. 350, Issue 6259, pp. 442-445, doi : 10.1126 / science.aad0836 .

Web links

This text is based in whole or in part on the entry Calcineurin in Flexikon , a wiki of the DocCheck company . The takeover took place on March 15, 2007 under the then valid GNU license for free documentation .