AUTHOR=Jamabo Miebaka , Bentley Stephen John , Macucule-Tinga Paula , Tembo Praise , Edkins Adrienne Lesley , Boshoff Aileen 

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

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.947078

DOI=10.3389/fmolb.2022.947078

ISSN=2296-889X

ABSTRACT=<p>African trypanosomiasis is a neglected tropical disease caused by <italic>Trypanosoma brucei</italic> (<italic>T. brucei</italic>) 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 <italic>in silico</italic> overview of HSP90 and its co-chaperones in both <italic>T. brucei brucei</italic> and <italic>T. brucei gambiense</italic> in relation to human and other trypanosomal species, including non-parasitic <italic>Bodo saltans</italic> and the insect infecting <italic>Crithidia fasciculata</italic>. A structural analysis of <italic>T. brucei</italic> HSP90 revealed differences in the orientation of the linker and C-terminal domain in comparison to human HSP90. Phylogenetic analysis displayed the <italic>T. brucei</italic> HSP90 proteins clustering into three distinct groups based on subcellular localizations, namely, cytosol, mitochondria, and endoplasmic reticulum. Syntenic analysis of cytosolic <italic>HSP90</italic> genes revealed that <italic>T. b. brucei</italic> encoded for 10 tandem copies, while <italic>T. b. gambiense</italic> encoded for three tandem copies; <italic>Leishmania major (L. major)</italic> had the highest gene copy number with 17 tandem copies. The updated information on HSP90 from recently published proteomics on <italic>T. brucei</italic> was examined for different life cycle stages and subcellular localizations. The results show a difference between <italic>T. b. brucei</italic> and <italic>T. b. gambiense</italic> with <italic>T. b. brucei</italic> encoding a total of twelve putative <italic>HSP90</italic> genes, while <italic>T. b. gambiense</italic> encodes five <italic>HSP90</italic> 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.</p>