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Calcineurin is a serine/threonine phosphatase that is activated by calmodulin in a calcium-dependant manner. Calcineurin is the only known calmodulin-activated protein phosphatase. Calcineurin is responsible mainly for dephosphorylating several member of the NFAT transcription factor family (including NFATc1 through NFATc4).
Localisation and expression:
Calcineurin is a cytoplasmic protein. The catalytic subunit calcineurin A, posses two major isoforms called calcineurin Aα and Aβ. Calcineurin Aα is widely expressed among tissues especially in the Central Nervous System (CNS). Calcineurin Aβ is rather found in the lymphoid cells.Calcineurin Aβ is therefore involved in the mediation of the immune response [3].
Function
General structure
is a heterodimeric Protein that consits of two subunits. They are called catalytic and regulatory subunit.
This structure presented in this article is the catalytic subunit isoform of the serine/threonine-protein phosphatase 2B in rattus norvegicus (rat). It consists of 521 [4] aminoacids and has a molecular weight of 57 kDa [5].
The calatytic subunit is subdivided into functional domains which are a , a , a and an .
Discovery of the structure:
The structure have been published in the year 2013 by Qilu Ye et al. [6]. For their experiments they used x-ray diffraction. The PDB validation obtained a Resolutionof 3.0 Å, a free R-value of 0.273 and a work R-value of 0.241 [7].
secondary structure:
The secondary structure includes mostly helical structures
Besides, there are six turns reported in the structure of a chain.
Mechanism of action
Addictional structural highlights
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Binding Partners
The main partners of interaction are Calmodulin,NFATc1, NFATc2 and NFATc3.
Many of the calcineurin substrates’ contain a PxIxIT motif. Among them, beside the phosphorylated forms of NFAT we can also mentioned; cAMP response element binding (CREB), PP1, microtubule-associated protein tau and glycogen synthase kinase-3 beta (GSK- 3)[8].
Calcineurin is inhibited by the immunosuppressive drugs tacrolismus (FK506) or cyclosporine A (CsA). CsA and FK506 conduct their therapeutic role thought binding to the immunophilins cyclophilin and FK506 binding protein (FK506BP) respectively. The complexes CsA-cyclophilin and FK506-FK506BP bind then to calcineurin in a calcium-dependent manner thus inhibiting its phosphatase activity. Therefore the addition of these drugs to lymphocytes T prevent NFAT translocation to the nucleus and the subsequent activation its target gene.That's why FK506 and CsA are use in the treatment of various immune-mediated diseases. However since calcineurin is is widely expressed in non-haemopoietic tissues like the kidney and the hearth, both drugs present a long term toxicity and can lead to deleterious effect to these organs[9], [10].
Cofactors:
Calcineurin belong to the family of metalloprotein. To conduct its activity it requires the presence of Fe3+ and Zn2+ ions in the active site (one per subunit).Superoxide dismutase has been shown to protect calcineurin from inactivation by preventing Fe3+ from oxidation. Thus after activation of calcineurin by calmodulin, the AID is displaced from the catalytic core exposing Fe3+ to oxidation[11][12].
Related health defects
