Hsp90 and Associated Co-Chaperones of the Malaria Parasite

Abstract

Heat shock protein 90 (Hsp90) is one of the major guardians of cellular protein homeostasis, through its specialized molecular chaperone properties. While Hsp90 has been extensively studied in many prokaryotic and higher eukaryotic model organisms, its structural, functional, and biological properties in parasitic protozoans are less well defined. Hsp90 collaborates with a wide range of co-chaperones that fine-tune its protein folding pathway. Co-chaperones play many roles in the regulation of Hsp90, including selective targeting of client proteins, and the modulation of its ATPase activity, conformational changes, and post-translational modifications. Plasmodium falciparum is responsible for the most lethal form of human malaria. The survival of the malaria parasite inside the host and the vector depends on the action of molecular chaperones. The major cytosolic P. falciparum Hsp90 (PfHsp90) is known to play an essential role in the development of the parasite, particularly during the intra-erythrocytic stage in the human host. Although PfHsp90 shares significant sequence and structural similarity with human Hsp90, it has several major structural and functional differences. Furthermore, its co-chaperone network appears to be substantially different to that of the human host, with the potential absence of a key homolog. Indeed, PfHsp90 and its interface with co-chaperones represent potential drug targets for antimalarial drug discovery. In this review, we critically summarize the current understanding of the properties of Hsp90, and the associated co-chaperones of the malaria parasite.

Heat shock protein 90: biological functions, diseases, and therapeutic targets

“…The cytosolic P. falciparum Hsp90 (PfHsp90) is a pivotal player in the development of the parasite, particularly during its intra-erythrocytic stage within the human host. 99 Protozoans, including Leishmania donovani and P. falciparum, the culprits behind leishmaniasis and malaria respectively, rely on HSP90 to navigate the temperature and pH variations they encounter throughout their life cycles, making the HSP90 system crucial for differentiation and development. 100,101 Consequently, the use of speciesspecific inhibitors targeting parasite HSP90 presents a promising approach to impede their proliferation.…”

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update

“…Since cytoplasmic human HSP90 is a specialized chaperone with many oncogenic client proteins, it has been extensively studied as an anticancer drug target, with many of the resulting inhibitors and drug candidates being readily accessible starting points for PfHSP90-based antimalarial drug discovery. Furthermore, while there is a 64% identity between cytosolic PfHSP90 and cytoplasmic human HSP90 (HSP90β), PfHSP90 has a number of distinct biochemical and structural differences ( Figure 1 ), 38 which have already been investigated but could be further explored. Inhibitors of HSP90 typically bind to the highly conserved ATP-binding site in the N-terminus, and this appears to be the case for many of the PfHSP90 inhibitors (harmine analogs, 2-aminobenzamides, amino-alcohol carbazoles, pyrimidinediones and terpenoids; Table 1 ).…”

“… 39 Thus, it will be important to exploit the subtle structural differences between PfHSP90 and human HSP90, 40 including the differences between their heterocomplexes with clients and cochaperones. 38 For example, the glycine-rich hinge loop (GHL) motif of the ATP-binding pocket of PfHSP90 forms a unique hydrophobic extension that could potentially be leveraged by analogs of some of the known HSP90 inhibitors. 41 Many of the known human HSP90 inhibitors, such as PU-H71 21 and geldanamycin, 42 have nanomolar activity against parasite growth, providing multiple, strong starting points.…”

New Insights into Hsp90 Structural Plasticity Revealed by cryoEM

“…In parasites, Hsp90 has several important roles, which can vary depending on the specific parasite species and its life cycle. Parasites rely on a variety of essential proteins for processes such as invasion, growth, stage conversion, host interaction, and evasion of the host's immune system [102,103]. When parasites encounter adverse conditions, such as changes in temperature, pH, or exposure to host immune responses, Hsp90 can assist in protecting and stabilizing essential proteins to help the parasite survive and adapt.…”