A Novel Class of Dual-family Immunophilins

Abstract

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. Structurefunction 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.

On the role, ecology, phylogeny, and structure of dual-family immunophilins

“…Cells with mutations in these genes grew as well as wild type in laboratory culture but were completely nonmotile. As mentioned earlier, our detailed biochemical studies characterized the GldI gene product as a CFBP (Adams et al 2005). Interestingly, three of the Gld genes comprised a putative ATP-binding cassette (ABC) transporter, a multisubunit complex (McBride 2004;Braun and McBride 2005).…”

“…As shown (Table 1), these proteins are relatively large or constitute multisubunit complexes, and some of them are also membrane-bound, playing a role in transport or motility. As mentioned earlier, two of the first discovered DFI genes were F. johnsoniae CFBPs (Adams et al 2005) and were located next to the GldI gene, one of several Gld family genes, essential for gliding motility and chitin utilization (McBride and Braun 2004). It is to be noted that the GldI gene itself codes for a membrane lipoprotein (McBride and Braun 2004) with a domain that shows strong homology to FKBP and thus may also act as a chaperone in conjunction with the two CYN-FKBP paralogs that we reported (Adams et al 2005).…”

“…As mentioned earlier, two of the first discovered DFI genes were F. johnsoniae CFBPs (Adams et al 2005) and were located next to the GldI gene, one of several Gld family genes, essential for gliding motility and chitin utilization (McBride and Braun 2004). It is to be noted that the GldI gene itself codes for a membrane lipoprotein (McBride and Braun 2004) with a domain that shows strong homology to FKBP and thus may also act as a chaperone in conjunction with the two CYN-FKBP paralogs that we reported (Adams et al 2005). One of the two CYN genes of Polaribacter dokdonensis, a flavobacterium (Yoon et al 2006), is a close neighbor of the CFBP gene (Table 1), perhaps suggesting a co-operative role.…”

“…Members of both CYN and FKBP classes primarily function as chaperones that assist and regulate the folding of client proteins. In 2005, our team reported the founding members of dual-family immunophilins (DFI) that were recognized as natural chimera of the catalytic modules of CYN and FKBP, joined in either order, by a linker region (Adams et al 2005;Barik 2006). Based on the order of the two modules, the DFIs were later subdivided into two types, with separate acronyms: CFBP (Cyclosporin-and FK506-binding protein, with the architecture CYN-linker-FKBP) and FCBP Electronic supplementary material The online version of this article (doi:10.1007/s12192-017-0813-x) contains supplementary material, which is available to authorized users.…”

Master and servant: Regulation of auxin transporters by FKBPs and cyclophilins

“…1). A family of chimeric immunophilins that contain both Cyp and FKBP domains was reported in Toxoplasma gondii and designated as FCBPs for FK506 and cyclosporin A binding proteins [51] but FCBPs do not appear broadly conserved across different species.…”