Abstract
The malaria parasite Plasmodium falciparum extensively modifies erythrocytes that it invades by exporting a large complement of proteins to the host cell. Among these exported components is a single heat-shock 70 kDa class protein, PfHsp70-x, that supports the virulence and growth rate of the parasite during febrile episodes. The ATP-binding domain of PfHsp70-x has previously been resolved and showed the presence of potentially druggable epitopes that differ from those on human Hsp70 chaperones. Here, the crystallographic structure of the substrate-binding domain (SBD) of PfHsp70-x is presented in complex with a hydrophobic peptide. The PfHsp70-x SBD is shown to be highly similar to the counterpart from a human erythrocytic Hsp70 chaperone. The binding of substrate at the interface between β-sandwich and α-helical subdomains of this chaperone segment is also conserved between the malaria parasite and humans. It is hypothesized that the parasite may partly exploit human chaperones for intra-erythrocytic trafficking and maintenance of its exported proteome.
Highlights
Malaria is an acute febrile illness caused by five different Plasmodium species in humans (World Health Organization, 2019)
The exported proteins include the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of adhesion ligands that mediate cell attachment (Hviid & Jensen, 2015), members of the Plasmodium helical interspersed sub-telomeric (PHIST) protein family that act as interaction hubs (Warncke et al, 2016), and parasite components that remodel the host membrane and cytoskeleton, create nutrient-permeability pathways and contribute to immune-system evasion
PfHsp70-x is found in the parasitophorous vacuole, where it may associate with the PTEX translocation machinery (Zhang et al, 2017), as well as in the host-cell cytoplasm, where it localizes in mobile structures, the ‘J-dots’, together with stimulatory Hsp40-class co-chaperones and the PfEMP1 adhesion ligand (Kulzer et al, 2012)
Summary
Malaria is an acute febrile illness caused by five different Plasmodium species in humans (World Health Organization, 2019). It is thought that PfHsp70-x assists in PfEMP1 folding and in the assembly of a virulence complex on the erythrocyte membrane that includes PfEMP1 Consistent with this analysis, parasite lines lacking PfHsp70-x exported PfEMP1 less efficiently and were $60% less adherent compared with control parasites (Charnaud et al, 2017). In addition to its role in parasite virulence, PfHsp70-x supports cell viability at elevated temperatures, as PfHsp70-x depletion reduced parasite growth by $40% during heat shocks comparable to the febrile episodes of malaria patients (Day et al, 2019). These studies have established PfHsp70-x as a key component for parasite survival and virulence. We show that the PfHsp70-x SBD is highly similar to the human erythrocytic chaperone Hsp in structure and mode of substrate binding
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