Export determinants and pathways in protein trafficking in the human malaria parasite Plasmodium falciparum

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Blood stages of the human malaria parasite Plasmodium falciparum are responsible for the disease malaria. In this life cycle phase the parasites multiply in human red blood cells. To turn this intracellular niche into an environment suitable for survival and growth, the parasite induces profound changes mediated by a large number of exported parasite proteins. Hence, exported proteins are of crucial importance for the parasite. These proteins have to be trafficked beyond the parasite boundary and across the surrounding parasitophorous vacuole membrane to reach the host cell. Recent data indicates that these steps are mediated by translocation events but the individual steps have not been resolved. Further, there are different types of exported proteins known, including many with a so called Plasmodium export element (PEXEL) and others without such a motif (PNEPs, PEXEL negative exported proteins). Both these groups comprise soluble as well as transmembrane proteins, requiring different translocation modi for export. While PEXEL proteins can be predicted based on the presence of a defined export motif, PNEPs can not be predicted and it is therefore unknown how many further exported proteins are encoded in the P. falciparum genome. In this application it is proposed to find the export-mediating sequence determinants in a recently discovered core export domain shared between PNEPs and PEXEL proteins to predict and identify further (potentially all) exported proteins in malaria parasites. Further we will identify the sequences mediating export of recently discovered new types of PNEPs and test whether they also contain the core export domain shared between PNEPs and PEXEL proteins. Finally we will analyse the pathway these proteins take into the host cell, with a focus on resolving the translocation steps in the parasite periphery that involve the parasite plasma membrane and the parasitophorous vacuole. Protein export to modify the highly derived host cell is necessary for parasite survival and is also responsible for changes to the host cell surface directly linked to parasite virulence. Knowing which proteins are exported and how they are exported is therefore not only a fascinating cell biological problem but may ultimately also provide new targets for chemotherapeutic interventions for this important parasite.