TyrTRYPs

Microtubules are major components of the eukaryotic cytoskeleton. They are assembled from dimers of a/ß-tubulin and involved in various key cellular processes. This functional diversity is regulated by the ‘tubulin code’ which combines the expression of different a/ß-tubulin isotypes with several reversible tubulin post-translational modifications. Among them, the importance of the a-tubulin tyrosination cycle, involving the cleavage and religation of a C-terminal tyrosine, has been clearly established in human health. This cycle only occurs on a-tubulin and serves as a readable code for the specific recruitment of microtubule-associated proteins. A unique feature in single-celled flagellated parasites from the trypanosomatid group is the presence of a non-canonical C-terminal tyrosine on the ß-tubulin gene. Leishmania spp., Trypanosoma cruzi and T. brucei, collectively known as the ‘TriTryps’, represent a strong human and economic burden which require new therapeutic approaches. Their cytoskeleton is essentially based on microtubules whose specialisation depend almost exclusively on post-translational modifications. The presence of the C-terminal tyrosine on ß-tubulin has the potential to reveal novel regulatory mechanisms important for all trypanosomatid infections. The goal of the TyrTRYPs project is to perform the first comprehensive study of ß-tubulin tyrosination as part of the trypanosomatid-specific ‘tubulin code’. This will be achieved through the following aims: (1) Explore the importance of ß-tubulin tyrosination and detyrosination for parasite development and virulence; (2) Define the ß-tubulin specific interactome depending on its tyrosination status. Altogether it will bring new insights into parasite-specific regulatory mechanisms that may be exploited to develop drugs against all medically important trypanosomatid parasites.