Comparative structure-function features of Hsp70s of Plasmodium falciparum and human origins

Abstract

The heat shock protein 70 (Hsp70) family of molecular chaperones are crucial for the survival and pathogenicity of the main agent of malaria, Plasmodium falciparum . Hsp70 is central to cellular proteostasis and some of its isoforms are essential for survival of the malaria parasite. In addition, they are also implicated in the development of antimalarial drug resistance. For these reasons, they are thought to be potential drug targets, especially in antimalarial combination therapies. However, their high sequence conservation across species presents a hurdle with respect to their selective targeting. The human genome encodes 17 Hsp70 isoforms while P. falciparum encodes for only 6 . The structural architecture of Hsp70s is typically characterized by a highly conserved N-terminal nucleotide-binding domain (NBD) and a less conserved C-terminal substrate-binding domain (SBD). The two domains are connected by a highly conserved linker. In spite of their fairly high sequence conservation, Hsp70s from various species possess unique signature motifs that appear to uniquely influence their function. In addition, their cooperation with co-chaperones further regulates their functional specificity. In the current review, bioinformatics tools were used to identify conserved and unique signature motifs in Hsp70s of P. falciparum versus their human counterparts. We discuss the common and distinctive structure-function features of these proteins. This information is important towards elucidating the prospects of selective targeting of parasite heat shock proteins as part of antimalarial design efforts.

Comparative characterisation ofPlasmodium falciparumHsp70-1 relative toE. coliDnaK reveals functional specificity of the parasite chaperone

“…Our findings do not only demonstrate the unique functional features between PfHsp70-1 and DnaK but also highlight the role of the SBD of Hsp70 in the interaction of this protein with nucleotide and the Hsp40 cochaperone. One of the key features that sets apart PfHsp70-1 and other cytosolic Hsp70s of parasitic origin is the prominent presence of GGMP repeat motifs located in the C-terminal SBD of this protein (1,6). The GGMP motif and other unique residues present in PfHsp70-1 may confer it with unique functional features.…”

“…This finding suggests that the NBD of DnaK and the SBD of PfHsp70-1 constituting the domains of KPf, create a structurally unique NBD:SBD interface that promotes efficient hydrolysis of ATP in the presence of PfHsp40. Since the NBD of Hsp70 is highly conserved while its SBD is fairly divergent, the NBD:SBD interface of Hsp70 is regarded as a unique structural entity that regulates its functional specificity (6). Some Hsp70s self-associate to form functional complexes that interact with cochaperones to facilitate substrate refolding (58).…”

“…This is important towards understanding its role in the survival of the parasite and validation of its utility as a possible antimalarial drug target. Notably, PfHsp70-1 and its homologues of parasitic origin are endowed with an extended GGMP repeat motif that is located in the C-terminal substrate binding domain (SBD) (6). The location of the GGMP motif in the SBD of PfHsp70-1 suggests possible roles of this motif in regulating substrate selection and interaction of the chaperone with its co-chaperones.…”

“…It was previously reported that PfHsp70-1 possesses higher basal ATPase activity compared to its human and E. coli Hsp70 homologues (3). The unique structure-function features of PfHsp70-1 in comparison to its human Hsp70, have spurred interest to target it as part of antimalarial drug design efforts (3,4,6). P. falciparum Hsp40 (PF3D7 -1437900) is a cochaperone of PfHsp70-1 that co-localises with it to the parasite cytosol (20).…”

Biophysical Reviews: promoting the African synchrotron facility, partnering with national biophysical societies, highlighting advances in structural biology

“…Continuing on with the structure-function theme, the next Review, by Dr. Lizelle Lubbe and Prof. Edward Sturrock of the University of Cape Town, provides latest insight into the search for improved inhibitors of angiotensin-converting enzyme (ACE-Inhibitors)-the major drug target in studies of hypertension (Lubbe and Sturock 2019). Exploring an interesting aspect of comparative structural biology, Mr. Graham Chakafana, Dr. Tawanda Zininga, and Prof. Addmore Shohnai of the University of Venda review potentially exploitable drug targets associated with differences in the composition and structure of the Hsp 70 class of heat shock proteins found in humans and the parasite responsible for malaria -Plasmodium falciparum (Chakafana et al 2019). The next Review by Dr. Michaela Conley and Prof. Graham Bhella of the University of Glasgow examine methods for cryo-electron microscopy-based structural analysis of viruses that are not dependent on an assumed symmetry of the viral capsid (Conley and Bhella 2019).…”