gms | German Medical Science

The most severe form of malaria is caused by the asexual development of the apicomplexan parasite Plasmodium falciparum within the red blood cell (RBC) and leads to almost one million deaths each year. In order to avoid splenic clearance the parasite transports adhesion molecules like PfEMP1 to the surface of the infected red blood cell (iRBC). PfEMP1 is responsible for endothelial binding of the iRBC, which in turn accounts for all pathology observed in malaria.

Recently, the conserved intracellular domain of PfEMP1 (ATS) was suggested to comprise conserved protein interaction epitopes (Mayer et al., 2012). Moreover it was shown that this domain interacts with the PHIST domain of PFI1780w, a member of the recently discovered Plasmodium helical interspersed sub-telomeric (PHIST) family (Sargeant et al., 2006). Therefore, we proposed that PHIST domains facilitate protein interactions, and that disruption of this interaction could interfere with the parasite’s cytoadherence.

In order to elucidate the localization of a subset of PHIST proteins including PFI1780w we performed a GFP/3xHA tagging approach. Besides PFI1780w which was found at the iRBC surface and membrane associated, another PHIST protein (PFE1605w) has been shown to localize to the knobs. We could show that the PHIST domain of PFE1605w binds with a 10x higher affinity (Kd ~3 µM) to the intracellular ATS domain of PfEMP1 than the previously reported PFI1780w. In contrast, no binding has been observed for MAL8P1.4, a PHIST protein which we have shown to localize to a subset of Maurer’s clefts.

Various localizations and binding properties of PHIST proteins suggest that diverse functions can be identified within this protein family and the PHIST domains of PFI1780w and PFE1605w are so far the only proteins found to bind to the intracellular ATS domain of PfEMP1. Moreover the cellular localizations of these two proteins are consistent with the binding of ATS.