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Abstract
The immunosuppressive drugs FK506 and rapamycin have anti-malarial properties but
their mechanisms of action against malaria parasites remain unknown. The pathway by
which these drugs cause immunosuppression in humans is known to involve an FK506-binding
protein (FKBP). Homologues of FKBPs have been identified in almost every organism
in which they have been sought. Here, we describe the characterisation of the first
member of the FKBP family identified in the human malarial parasite, Plasmodium falciparum.
This 35-kDa protein, PfFKBP35, comprises a single, N-terminal, FKBP domain and a C-terminal
tripartite tetratricopeptide repeat domain. A recombinant form of PfFKBP35, like most
other FKBPs, displayed peptidyl-prolyl cis-trans isomerase activity that was inhibitable
by FK506 and rapamycin. Unusually the phosphatase activity of calcineurin, the target
of the FK506-FKBP complex in T-lymphocytes, was inhibited by PfFKBP35 independently
of FK506 binding. PfFKBP35 also inhibited the thermal aggregation in vitro of two
model substrates, suggesting that it has general chaperone properties. Analysis of
the P. falciparum genome database suggested this to be the only FKBP present in the
parasite. The function of this protein remains unknown but the presence of tetratricopeptide
repeat motifs suggests a role in intracellular protein transport or modulation of
protein function.