In silico analysis of the HSP90 chaperone system from the African trypanosome, Trypanosoma brucei

Abstract

African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei (T. brucei) and spread by the tsetse fly in sub-Saharan Africa. The trypanosome relies on heat shock proteins for survival in the insect vector and mammalian host. Heat shock protein 90 (HSP90) plays a crucial role in the stress response at the cellular level. Inhibition of its interactions with chaperones and co-chaperones is being explored as a potential therapeutic target for numerous diseases. This study provides an in silico overview of HSP90 and its co-chaperones in both T. brucei brucei and T. brucei gambiense in relation to human and other trypanosomal species, including non-parasitic Bodo saltans and the insect infecting Crithidia fasciculata. A structural analysis of T. brucei HSP90 revealed differences in the orientation of the linker and C-terminal domain in comparison to human HSP90. Phylogenetic analysis displayed the T. brucei HSP90 proteins clustering into three distinct groups based on subcellular localizations, namely, cytosol, mitochondria, and endoplasmic reticulum. Syntenic analysis of cytosolic HSP90 genes revealed that T. b. brucei encoded for 10 tandem copies, while T. b. gambiense encoded for three tandem copies; Leishmania major (L. major) had the highest gene copy number with 17 tandem copies. The updated information on HSP90 from recently published proteomics on T. brucei was examined for different life cycle stages and subcellular localizations. The results show a difference between T. b. brucei and T. b. gambiense with T. b. brucei encoding a total of twelve putative HSP90 genes, while T. b. gambiense encodes five HSP90 genes. Eighteen putative co-chaperones were identified with one notable absence being cell division cycle 37 (Cdc37). These results provide an updated framework on approaching HSP90 and its interactions as drug targets in the African trypanosome.

Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

“…The T. brucei molecular chaperone network is implicated in survival, differentiation, and pathogenicity, as well as coping with environmental stressors [246][247][248][249]. An analysis of the molecular chaperone machinery in T. brucei revealed an expansion in the number of J-proteins and Hsp70 proteins, indicating that these protein families may play a critical role in the biology of the parasite [250]. Co-chaperones of T. brucei Hsp90 were recently identified, and it is possible that chaperone/co-chaperone interactions could be pursued as potential drug targets [251].…”

“…TbHsp70.c possesses a divergent linker region, and substitutions at otherwise highly conserved amino acid residues within the substrate-binding pocket [256]. Furthermore, TbHsp70.c lacks the EEVD motif, which is essential for interacting with TPR domain-containing co-chaperones, such as the stress-inducible phosphoprotein 1 (STI1) [250,254]. STI1 serves as a regulator of substrate channeling between Hsp70 and Hsp90, and TbHsp70.c does not interact with T. brucei STI1 [256,257].…”