Abstract
Plasmodium falciparum, the main agent of malaria expresses six members of the heat shock protein 70 (Hsp70) family. Hsp70s serve as protein folding facilitators in the cell. Amongst the six Hsp70 species that P. falciparum expresses, Hsp70‐x (PfHsp70‐x), is partially exported to the host red blood cell where it is implicated in host cell remodeling. Nearly 500 proteins of parasitic origin are exported to the parasite‐infected red blood cell (RBC) along with PfHsp70‐x. The role of PfHsp70‐x in the infected human RBC remains largely unclear. One of the defining features of PfHsp70‐x is the presence of EEVN residues at its C‐terminus. In this regard, PfHsp70‐x resembles canonical eukaryotic cytosol‐localized Hsp70s which possess EEVD residues at their C‐termini in place of the EEVN residues associated with PfHsp70‐x. The EEVD residues of eukaryotic Hsp70s facilitate their interaction with co‐chaperones. Characterization of the role of the EEVN residues of PfHsp70‐x could provide insights into the function of this protein. In the current study, we expressed and purified recombinant PfHsp70‐x (full length) and its EEVN minus form (PfHsp70‐xT). We then conducted structure‐ function assays towards establishing the role of the EEVN motif of PfHsp70‐x. Our findings suggest that the EEVN residues of PfHsp70‐x are important for its ATPase activity and chaperone function. Furthermore, the EEVN residues are crucial for the direct interaction between PfHsp70‐x and human Hsp70‐Hsp90 organizing protein (hHop) in vitro. Hop facilitates functional cooperation between Hsp70 and Hsp90. However, it remains to be established if PfHsp70‐x and hHsp90 cooperate in vivo.
Highlights
Malaria persists as a major cause of morbidity and deaths around the world, with the latest data showing that it accounts for ~450 000 deaths annually.[1]
It was important to establish that recombinant proteins (PfHsp70-x and PfHsp70-xT) would not aggregate at 48C (Figure 4A,B). This is in line with our circular dichroism (CD) data that showed that both PfHsp70-x and PfHsp70-xT are generally stable at high temperatures as up to 50% of the proteins remained folded at temperatures as high as 70C (Figure 1B)
We sought to establish the substrate preferences of PfHsp70-x as such information could shed light on its role both in the trafficking and proteostasis of parasite proteins destined for the red blood cell (RBC)
Summary
Malaria persists as a major cause of morbidity and deaths around the world, with the latest data showing that it accounts for ~450 000 deaths annually.[1]. We investigated the substrate binding preferences of PfHsp70-x
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