Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte

During their intraerythrocytic development, malaria parasites export hundreds of proteins to remodel their host cell. Nutrient acquisition, cytoadherence and antigenic variation are among the key virulence functions effected by this erythrocyte takeover. Proteins destined for export are synthesized in the endoplasmic reticulum (ER) and cleaved at a conserved (PEXEL) motif, which allows translocation into the host cell via an ATP-driven translocon called the PTEX complex. We report that plasmepsin V, an ER aspartic protease with distant homology to the mammalian processing enzyme BACE, recognizes the PEXEL motif and cleaves it at the correct site. This enzyme is essential for parasite viability and ER residence is essential for its function. We propose that plasmepsin V is the PEXEL protease and is an attractive enzyme for antimalarial drug development. The human malaria parasite Plasmodium falciparum exports an estimated 200–300 proteins into the host erythrocyte1,2. In doing so, the parasite remodels the cytoskeleton and plasma membrane to create cytoadherence knobs, nutrient permeation pathways and altered erythrocyte mechanical stability3,4. Export of these effectors is dependent on a Plasmodium export element or PEXEL sequence, RxLxE/Q/D5,6. Proteins destined for export are cleaved after the conserved PEXEL leucine in the ER and mutation of the R or L residues attenuates cleavage and export7,8. Plasmepsin V (PM V) is an aspartic protease that has distant homology to mammalian BACE or beta-secretase9, an enzyme involved in the processing of amyloid precursor protein10. Both have a C-terminal extension that contains a hydrophobic membrane anchor sequence. An N-terminal aspartic protease “pro-domain” remains unprocessed in PM V9. PM V is expressed in intraerythrocytic P. falciparum Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use