The FK506-binding protein of the malaria parasite, Plasmodium falciparum, is a FK506-sensitive chaperone with FK506-independent calcineurin-inhibitory activity.
We have identified an immunophilin of the FKBP family in Plasmodium falciparum that contains a conserved peptidyl prolyl isomerase (PPIase) and tetratricopeptide repeat (TPR) domains. The 35 kDa protein was named FKBP35 and expressed in bacteria. Recombinant FKBP35 exhibited potent PPIase and protein folding activities against defined substrates in vitro, suggesting that it is a parasitic chaperone. Both activities were inhibited by macrolide immunosuppressant drugs, ascomycin (a FK506 derivative) and rapamycin, but not by cyclosporin A, providing biochemical evidence of its inclusion in the FKBP family. Interestingly, FKBP35 inhibited purified plasmodial calcineurin (protein phosphatase 2B) in the absence of any drug. In the parasite's cell, FKBP35 exhibited a stage-specific nucleocytoplasmic shuttling and did not co-localize with calcineurin. FKBP35 associated with plasmodial heat shock protein 90 (Hsp90), another member of the chaperone superfamily, via the TPR domain. Geldanamycin, a Hsp90 inhibitor, and ascomycin inhibited P. falciparum growth in a synergistic fashion. Extensive search of the P. falciparum genome revealed no other FKBP sequence, implicating PfFKBP35 as a highly significant antimalarial drug target. Thus, the single FKBP of Plasmodium is an essential parasitic chaperone with a novel drug-independent calcineurin-inhibitory activity.
Kumar
Rajinder
R
Department of Biochemistry and Molecular Biology, University of South Alabama, College of Medicine, 307 University Blvd., Mobile, AL 36688-0002, USA.
Adams
Brian
B
Musiyenko
Alla
A
Shulyayeva
Olena
O
Barik
Sailen
S
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D020134:Catalytic Domain; D002467:Cell Nucleus / Q000737:chemistry; D016572:Cyclosporine / Q000494:pharmacology; D003593:Cytoplasm / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D000962:Antimalarials; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D016572:Cyclosporine; C058028:immunomycin; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus