Publications & Reports

Inhibition of Plasmodium falciparum CDPK1 by conditional expression of its J-domain demonstrates a key role in schizont development.

Azevedo MF, Sanders PR, Krejany E, Nie CQ, Fu P, Bach LA, Wunderlich G, Crabb BS, Gilson PR


Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) is highly expressed in parasite asexual blood and mosquito stages. Its role is still poorly understood, but unsuccessful gene knockout attempts suggest it is essential for schizont development and/or RBC invasion. Here, by tagging endogenous CDPK1 with GFP, we demonstrate that CDPK1 localises to the parasite plasma membrane of replicating and invasive forms as well as very young intracellular parasites and does not appear to be exported into the erythrocyte. While a knockdown of endogenous CDPK1 was achieved using a destabilization domain, parasites tolerated reduced expression without displaying a phenotype. Because of this, the PfCDPK1 auto-inhibitory junction region (J) was explored as a means of achieving inducible and specific inhibition. Under in vitro conditions, a fusion protein comprising a J-GFP fusion specifically bound to PfCDPK1 and inhibited its activity. This fusion protein was conditionally expressed in P. falciparum asexual blood stages under the regulation of a destabilization domain (J-GFP-DD). We demonstrate that J-GFP-DD binds to CDPK1 and that this results in the arrest of parasite development late in the cell cycle during early schizogony. These data point to an early schizont function for PfCDPK1 and demonstrates that conditionally expressing auto-inhibitory regions can be an effective way to address the function of Plasmodium enzymes.

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  • Journal: The Biochemical Journal
  • Published: 03/04/2013
  • Volume: 452
  • Issue: 3
  • Pagination: 433-441