Identification of Calcineurin Binding Sites May Improve Immunosuppressant Therapy

Immunologists have identified the site of interaction between immunosuppressant drugs such as cyclosporin and FK506 and their molecular target, the protein phosphatase calcineurin.

Calcineurin is a protein phosphatase also known as protein phosphatase 2B (PP2B). It is responsible for activating the transcription of interleukin 2 (IL-2), which stimulates the growth and differentiation of the T cell response. Calcineurin dephosphorylates a protein called nuclear factor of activated T cell, cytoplasmic component (NFATc), a transcription factor that migrates into the nucleus and activates the genes involved in IL-2 synthesis. In immunosuppressive therapy calcineurin is inhibited by the "calcineurin inhibitors" cyclosporin, pimecrolimus (Elidel), and tacrolimus (FK506).

Investigators at the Centro Nacional de Investigaciones Cardiovasculares (Madrid, Spain) reported in the March 13, 2009, issue of the journal Molecular Cell that NFATc interacted with calcineurin through distinct binding motifs: the PxIxIT and LxVP sites. Although many calcineurin substrates contain PxIxIT motifs, the generality of LxVP-mediated interactions has been unclear. In the current study they defined critical residues in the LxVP motif and demonstrated its binding to a hydrophobic pocket at the interface of the two calcineurin subunits. LxVP-type sites are a common feature of calcineurin substrates, and immunosuppressant-immunophilin complexes inhibited calcineurin by interfering with this mode of substrate recognition.

"Cyclosporin and FK506 each form complexes with specific immunophilin binding proteins and it is these complexes, called IS-IP complexes, that inhibit calcineurin activity," explained senior author Dr. Juan Miguel Redondo, professor of vascular biology and inflammation at the Centro Nacional de Investigaciones Cardiovasculares. "We showed that IS-IP complexes compete for binding to the same docking surface in calcineurin that mediates interactions with natural substrates, thereby blocking calcineurin signaling."
"Many of the severe side effects of FK506 and cyclosporin, such as neurotoxicity, diabetes, kidney dysfunction, and hypertension, are at least partly independent of calcineurin," said Dr. Redondo. "Identifying selective calcineurin inhibitors that avoid these secondary effects is of high interest."

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Centro Nacional de Investigaciones Cardiovasculares