Investigador Principal: ANTONIO RODRÍGUEZ

The calcium-sensitive phosphatase calcineurin, CN (also called protein phosphatase 2B) is implicated in many eukaryotic activation and developmental programmes, including lymphocyte activation, heart-valve morphogenesis, angiogenesis, and neural and muscle development.

Figure 1. Overall architecture of Calcineurin. Space-filling representation of the L-shaped structure of the catalytic subunit, CnA, bound to the regulatory subunit, CnB (shown in orange). CnA contains a phosphatase domain (shown in yellow) and a regulatory region, linked by a short sequence known as linker (shown in grey). The regulatory region contains a CnB-binding helical domain (shown in purple), a calmodulin binding region (CaMBR), and an autoinhibitory loop (shown in red). Residues corresponding to CaMBR and the C-terminal region are not visible in the crystals.

 

The importance of this phosphatase is graphically illustrated by the observation that the immunosuppressive actions of the microbial drugs Cyclosporin A (CsA) and FK506 arise from their inhibition of CN. As substrates of calcineurin, transcription factors of the NFAT (Nuclear Factor of Activated T-cells) family play an essential role in lymphocyte activation, and it follows that their function is also inhibited by CsA and FK506. Although the use of these drugs has been crucial for the success of organ transplantation, their therapeutic use is associated with severe side effects. Our current research interest is focused on a detailed analysis of the CN specific sequences involved in the interaction with the two CN-binding sites of NFAT, PxIxIT and LxVP motifs. A better knowledge of the specificity and regulation of NFAT-calcineurin interactions may lead to the development of more specific inhibitors of calcineurin. Reagents that exploit the selective interaction of CN with NFAT would be of use in dissecting important biological processes in which the CN/NFAT pathway plays a key role.

 

Figure 2. The Calcineurin-NFAT signalling pathway. An increase of intracellular calcium levels activates the cellular phosphatase Calcineurin (CN) through its interaction with Calmodulin (CaM). Activated CN is able to dephosphorylate NFAT (Nuclear Factor of Activtated T-cells), and allows the nuclear translocation of this transcription factor. In the nucleus, NFAT binds to specific DNA motifs within the promoter of numerous genes and induce their transcription.