A novel class of dual-family immunophilins

作者：Adams B; Musiyenko A; Kumar R; Barik S^*

来源：Journal of Biological Chemistry, 2005, 280(26): 24308-24314.

DOI：10.1074/jbc.M500990200

Immunophilins are protein chaperones with peptidylprolyl isomerase activity that belong to one of two large families, the cyclosporin- binding cyclophilins ( CyPs) and the FK506- binding proteins ( FKBPs). Each family displays characteristic and conserved sequence features that differ between the two families. We report a novel group of dual- family immunophilins that contain both CyP and FKBP domains for which we propose the name FCBP ( FK506- and cyclosporin- binding protein). The FCBP of Toxoplasma gondii, a protozoan parasite, contained N- terminal FKBP and C- terminal CyP domains joined by tetratricopeptide repeats. Structure function analysis revealed that both domains were functional and exhibited family- specific drug sensitivity. The individual domains of FCBP inhibited calcineurin ( protein phosphatase 2B) in the presence of the appropriate drugs. In binding studies, FCBP recruited calcineurin in the presence of FK506 and a putative target of rapamycin homolog in the presence of rapamycin. Two additional FCBP sequences in Flavobacterium and one in Treponema ( spirochete) were also identified in which the CyP and FKBP domains were in the reverse order. T. gondii growth was inhibited by cyclosporin and FK506 in a moderately synergistic manner. The knockdown of FCBP by RNA interference revealed its essentiality for T. gondii growth. Clearly, the FCBPs are novel chaperones and potential targets of multiple immunosuppressant drugs.

• 出版日期2005-7-1