Abstract
Plasmodium falciparum is the most lethal of human-infective malaria parasites. A hallmark of P. falciparum malaria is extensive remodeling of host erythrocytes by the parasite, which facilitates the development of virulence properties such as host cell adhesion to the endothelial lining of the microvasculature. Host remodeling is mediated by a large complement of parasite proteins exported to the erythrocyte; among them is a single heat shock protein (Hsp)70–class protein chaperone, P. falciparum Hsp70-x (PfHsp70-x). PfHsp70-x was previously shown to assist the development of virulent cytoadherence characteristics. Here, we show that PfHsp70-x also supports parasite growth under elevated temperature conditions that simulate febrile episodes, especially at the beginning of the parasite life cycle when most of host cell remodeling takes place. Biochemical and biophysical analyses of PfHsp70-x, including crystallographic structures of its catalytic domain and the J-domain of its stimulatory Hsp40 cochaperone, suggest that PfHsp70-x is highly similar to human Hsp70 chaperones endogenous to the erythrocyte. Nevertheless, our results indicate that selective inhibition of PfHsp70-x function using small molecules may be possible and highlight specific sites of its catalytic domain as potentially of high interest. We discuss the likely roles of PfHsp70-x and human chaperones in P. falciparum biology and how specific inhibitors may assist us in disentangling their relative contributions.—Day, J., Passecker, A., Beck, H.-P., Vakonakis, I. The Plasmodium falciparum Hsp70-x chaperone assists the heat stress response of the malaria parasite.
Highlights
Despite substantial progress during the last 2 decades, malaria still remains one of the most lethal infectious diseases in tropical countries, causing an estimated 435,000 deaths a year, primarily in sub-Saharan Africa and southeast Asia [1]
In order to evaluate the contribution of PfHsp70-x to parasite stress response, we used the influenza hemagglutinin (HA)-tag and glmSincorporating parasite line developed by Cobb et al (PfHsp70-xglmS) and initially heat shocked unsynchronized parasites to 40°C for 12 h prior to retuning them to standard conditions for the remainder of the parasite 48 h–long life cycle
We found no statistically significant effect on parasite growth upon PfHsp70-x depletion under these conditions; we noted that cell growth was highly variable, which impacted the statistical analysis
Summary
Despite substantial progress during the last 2 decades, malaria still remains one of the most lethal infectious diseases in tropical countries, causing an estimated 435,000 deaths a year, primarily in sub-Saharan Africa and southeast Asia [1]. ABBREVIATIONS: AMP-PnP, adenylyl-imidodiphosphate; BBL, bromob-lapachona; GlcN, glucosamine; glmS, GlcN-6-phosphate riboswitch; HA, influenza hemagglutinin; hpi, hours postinfection; HRP, horseradish peroxidase; Hsc, heat shock cognate protein 70; Hsp, heat shock protein; HSPA, heat shock protein family A; ID, identifier; MESG, 2-amino-6mercapto-7-methylpurine riboside; NBD, nucleotide-binding domain; PDB, Protein Data Bank; PEG, polyethylene glycol; PfEMP1, P. falciparum erythrocyte membrane protein 1; PfHsp70-x, P. falciparum Hsp70-x; RMSD, root mean square deviation; SBD, substrate-binding domain. Key to P. falciparum lethality is the extensive remodeling of its host cell, the human erythrocyte, for which it employs a larger proportion of its proteome (;10%, ;500 proteins) than any other human-infective malaria parasite [3]. The P. falciparum genome encodes numerous molecular chaperones thought to aid in coping with the stress of
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
