Diversity and genome mapping assessment of disordered and functional domains in trypanosomatids

Abstract

The proteins that have structural disorder exemplify a class of proteins which is part of a new frontier in structural biology that demands a new understanding of the paradigm of structure/function correlations. In order to address the location, relative distances and the functional/structural correlation between disordered and conserved domains, consensus disordered predictions were mapped together with CDD domains in Leishmania braziliensis M2904, Leishmania infantum JPCM5, Trypanosoma cruzi CL-Brener Esmeraldo-like, Trypanosoma cruzi Dm28c, Trypanosoma cruzi Sylvio X10, Blechomonas ayalai B08-376 and Paratrypanosoma confusum CUL13 predicted proteomes. Our results depicts the role of protein disorder in key aspects of parasites biology highlighting: a) statistical significant association between genome structural location of protein disordered consensus stretches and functional domains; b) that disordered protein stretches appear in greater percentage at upstream or downstream position of the predicted domain; c) a possible role of structural disorder in several gene expression, control points that includes but are not limited to: i) protein folding; ii) protein transport and degradation; and iii) protein modification. In addition, for values of protein with disorder content greater than 40%, a small percentage of protein binding sites in IDPs/IDRs, a higher hypothetical protein annotation frequency was observed than expected by chance and trypanosomatid multigene families linked with virulence are rich in protein with disorder content. SIGNIFICANCE: T. cruzi and Leishmania spp are the etiological agents of Chagas disease and leishmaniasis, respectively. Currently, no vaccine or effective drug treatment is available against these neglected diseases and the knowledge about the post-transcriptional and post-translational mechanisms of these organisms, which are key for this scenario, remain scarce. This study depicts the potential impact of the proximity between protein structural disorder and functional domains in the post-transcriptional regulation of pathogenic versus human non-pathogenic trypanosomatids. Our results revealed a significant statistical relationship between the genome structural locations of these two variables and disordered regions appearing more frequently at upstream or downstream positions of the CDD locus domain. This flexibility feature would maintain structural accessibility of functional sites for post-translational modifications, shedding light into this important aspect of parasite biology. This hypothesis is corroborated by the functional enrichment analysis of disordered proteins subset that highlight the involvement of this class of proteins in protein folding, protein transport and degradation and protein modification. Furthermore, our results pointed out: a) the impact of protein disorder in the process of genome annotation (proteins tend to be annotated as hypothetical when the disorder content reaches ~40%); b) that trypanosomatid multigenic families linked with virulence have a key protein disorder content.

Keywords: Functional domains; Multigene; Structural disorder; Trypanosomatids.