PfHsp40

Global efforts to eradicate malaria are threatened by multiple factors, particularly the emergence of anti-malarial drug resistant strains of Plasmodium falciparum. Heat shock proteins (HSPs), particularly P. falciparum HSPs (PfHSPs), represent promising drug targets due to their essential roles in parasite survival and virulence across the various life cycle stages. Despite structural similarities between human and malarial HSPs posing challenges, there is substantial evidence for subtle differences that could be exploited for selective drug targeting...

Here, we present data on characterisation of the linker of Plasmodium falciparum Hsp110 (PfHsp70-z) relative to the linker of canonical Hsp70s in support of a co-published article [1]. The linker of PfHsp70-z was switched with that of canonical Hsp70s, represented by PfHsp70-1 (cytosolic counterpart of PfHsp70-z) and E. coli Hsp70/DnaK. The datasets represent comparative analyses of PfHsp70-z, PfHsp70-1, and E. coli DnaK, relative to their linker switch mutants; PfHsp70-zLS , PfHsp70-1LS , DnaKLS , respectively...

Plasmodium falciparum has the most adenine (A)- and thymine (T)-rich genome known to date, and 24-30% of the P. falciparum proteome contains asparagine (N) and glutamine (Q) residues. In general, asparagine repeats in proteins increase the propensity for aggregation, especially at elevated temperatures, which occur routinely in P. falciparum parasites during exoerythrocytic and erythrocytic developmental stages in a vertebrate host. The P. falciparum exported chaperone machinery is comprised of an exported PfHsp70-x protein and its co-chaperone PfHsp40-x1 in the host erythrocyte compartment, and PfHsp70-z and its co-chaperones in the parasite cytoplasm have been identified...

Plasmodium falciparum, the human malaria parasite harbors a metastable proteome which is vulnerable to proteotoxic stress conditions encountered during its lifecycle. How parasite's chaperone machinery is able to maintain its aggregation-prone proteome in functional state, is poorly understood. As HSP70-40 system forms the central hub in cellular proteostasis, we investigated the protein folding capacity of PfHSP70-1 and PfHSP40 chaperone pair and compared it with human orthologs (HSPA1A and DNAJA1). Despite structural similarity, we observed that parasite chaperones and their human orthologs exhibit striking differences in conformational dynamics...

Plasmodium falciparum displays a large and remarkable variety of heat shock protein 40 family members (PfHsp40s). The majority of the PfHsp40s are poorly characterized, and although the functions of some of them have been suggested, their exact mechanism of action is still elusive and their interacting partners and client proteins are unknown. The P. falciparum heat shock protein 70 family members (PfHsp70s) have been more extensively characterized than the PfHsp40s, with certain members shown to function as molecular chaperones...

Malaria parasites modify their host cell, the mature human erythrocyte. We are interested in the molecules mediating these processes, and have recently described a family of parasite-encoded heat shock proteins (PfHsp40s) that are targeted to the host cell, and implicated in host cell modification. Hsp40s generally function as co-chaperones of members of the Hsp70 family, and until now it was thought that human Hsp70 acts as the PfHsp40 interaction partner within the host cell. Here we revise this hypothesis, and identify and characterize an exported parasite-encoded Hsp70, referred to as PfHsp70-x...

Heat shock protein 70 (Hsp70) and heat shock protein 40 (Hsp40) function as molecular chaperones during the folding and trafficking of proteins within most cell types. However, the Hsp70-Hsp40 chaperone partnerships within the malaria parasite, Plasmodium falciparum, have not been elucidated. Only one of the 43 P. falciparum Hsp40s is predicted to be a cytosolic, canonical Hsp40 (termed PfHsp40) capable of interacting with the major cytosolic P. falciparum-encoded Hsp70, PfHsp70. Consistent with this hypothesis, we found that PfHsp40 is upregulated under heat shock conditions in a similar pattern to PfHsp70...