Abstract
Hsp90 is considered to be the master regulator of chaperone activity within the cellular context. In addition to aiding client maturation and maintaining protein homeostasis, Hsp90 serves various non-canonical functions in model eukaryotes: ranging from protein-trafficking into the nucleus to transcriptional regulation, from chromatin remodeling to assembly and disassembly of protein complexes during DNA repair and telomere maintenance. In performing all these trades, Hsp90 collaborates with its co-chaperones in a client-specific or function-specific manner. Hsp90 undergoes various conformational changes during its chaperone cycle, which is regulated via several post-translational modifications (PTM). Different combinations of such PTMs, known as the chaperone code, also play key regulatory roles for Hsp90 functions. Here, we examine various cellular functions of Hsp90 in protozoan parasites, particularly those that shuttle between insect host and human host, adapting to a temperature difference of at least 10°C. Our analyses reveal that most of the prominent co-chaperones are present in all these parasites, except for one that is essential in model eukaryotes. We reviewed the biochemical correlates of Hsp90 and its co-chaperone interactions and realized that the physiological significance of such interplay is largely unknown in the protozoan parasites. One striking observation is the lack of sequence conservation of the parasitic co-chaperones with their human counterparts, making them attractive drug targets. Our analyses revealed that in spite of the identification of few PTMs of parasitic Hsp90 proteins, the chaperone codes remain largely elusive.IMPORTANCEHsp90 is a pivotal molecular chaperone involved in maintaining proteostasis and facilitating the maturation of diverse client proteins. Beyond its canonical folding functions, Hsp90 plays non-canonical roles in nuclear trafficking, transcriptional regulation, chromatin remodeling, and DNA repair. These activities are tightly regulated through interactions with specific co-chaperones and through post-translational modifications, collectively forming the "chaperone code." This study examines Hsp90's role in thermal adaptation of protozoan parasites when shuttling between the insect and human hosts. Here, we summarize the canonical and diverse non-canonical functions of Hsp90 in three protozoan parasites: Plasmodium, Leishmania, and Trypanosoma. We highlight all the Hsp90 isoforms found in these three parasites and also illustrate all the co-chaperones and post-translational modifications of Hsp90 found to be present in these protozoan parasites. Importantly, the divergence in co-chaperone sequences from human homologs in these parasites presents a promising avenue for targeted antiparasitic drug discovery and development.