Beyond the catalysis of Trypanosoma cruzi trans-sialidases: structure, function, post-translational modifications, intrinsically disordered regions and use of CRISPR/Cas9

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a global health problem with limited treatment options. The parasite’s trans-sialidase (TS) protein family has been widely described as a key component in its life cycle. In this work, we present a comprehensive review of the TS family, including its molecular structure, phylogenetic relationships, and known functions. Based on in silico analyses, we propose that intrinsically disordered regions (IDRs) present in the TS family may play a role in the spatial organization of these proteins. We also hypothesize that these IDRs could contribute to the formation of biomolecular condensates through liquid-liquid phase separation, providing a potential dynamic platform that is not fully explained by conventional structural models. In addition, we discuss recent advances in the application of the CRISPR/Cas9 gene-editing system to T. cruzi TS proteins. The available evidence indicates the multifunctional nature of these proteins, including enzymatic and non-enzymatic isoforms, as well as the presence of conserved motifs associated with host interactions and post-translational modifications. Taken together, this review integrates previous findings and proposes new hypotheses regarding additional functions of the TS family. The need for experimental studies to validate these proposals and clarify their relevance to the parasite’s biology is emphasized. This approach could contribute to evaluating the potential of TS as a therapeutic target in Chagas disease.