The TriTryp Phosphatome: analysis of the protein phosphatase catalytic domains

Abstract

BackgroundThe genomes of the three parasitic protozoa Trypanosoma cruzi, Trypanosoma brucei and Leishmania major are the main subject of this study. These parasites are responsible for devastating human diseases known as Chagas disease, African sleeping sickness and cutaneous Leishmaniasis, respectively, that affect millions of people in the developing world. The prevalence of these neglected diseases results from a combination of poverty, inadequate prevention and difficult treatment. Protein phosphorylation is an important mechanism of controlling the development of these kinetoplastids. With the aim to further our knowledge of the biology of these organisms we present a characterisation of the phosphatase complement (phosphatome) of the three parasites.ResultsAn ontology-based scan of the three genomes was used to identify 86 phosphatase catalytic domains in T. cruzi, 78 in T. brucei, and 88 in L. major. We found interesting differences with other eukaryotic genomes, such as the low proportion of tyrosine phosphatases and the expansion of the serine/threonine phosphatase family. Additionally, a large number of atypical protein phosphatases were identified in these species, representing more than one third of the total phosphatase complement. Most of the atypical phosphatases belong to the dual-specificity phosphatase (DSP) family and show considerable divergence from classic DSPs in both the domain organisation and sequence features.ConclusionThe analysis of the phosphatome of the three kinetoplastids indicates that they possess orthologues to many of the phosphatases reported in other eukaryotes, including humans. However, novel domain architectures and unusual combinations of accessory domains, suggest distinct functional roles for several of the kinetoplastid phosphatases, which await further experimental exploration. These distinct traits may be exploited in the selection of suitable new targets for drug development to prevent transmission and spread of the diseases, taking advantage of the already extensive knowledge on protein phosphatase inhibitors.

Host-Parasite Interactions in Trypanosomiasis: on the Way to an Antidisease Strategy

“…As great achievements in AT have been made by using comparisons with malaria and leishmaniasis, such a comparative approach among trypanosomiases could be fruitful (62,79,146). In this context, the Tritryp project, which involves jointly analyzing genomes and proteomes of T. brucei brucei, Trypanosoma cruzi, and Leishmania major, highlights the remarkably conserved genetic core between these species (23,38,62,125). Several genome projects are also under way for T. brucei gambiense, T. congolense, and T. vivax (62).…”

Protein phosphatase PP2C in the flagellum of Leishmania major: cloning and characterization

“…Secondary structure prediction was carried out using PSIPRED Protein Sequence Analysis Workbench version 3.3 (http://bioinf.cs.ucl.ac.uk/psipred/) (Melo et al 2002;Arnold et al 2006;Shen and Sali, 2006;Bordoli et al 2009;Guex et al 2009;Buchan et al 2013;Biasini et al 2014).…”

Cell Signaling During Trypanosoma cruzi Development in Triatominae

“…Also, different groups have analyzed genes coding for PTPs, which has provided interesting data. The T. cruzi genome codes for only two intracellular, classical PTPs, fully dedicated enzymes for tyrosine dephosphorylation [64][65][66]. Therefore, if PTPs evolved independently several times, it is likely that protozoan enzymes display unique structural motifs or mechanism of regulation, which could allow for the development of specific chemotherapies [67].…”

“…In this context, drugs that act by modulating signal transduction pathways are particularly interesting. Although this matter remains largely unexplored in trypanosomatids, recent work has generated promising data [60,63,64,[68][69][70]. A comparative study of the kinomes of trypanosomatids T. brucei, T. cruzi and Leishmania major showed that approximately 12% of their kinases are unique to trypanosomatids [63,69].…”

“…A comparative study of the kinomes of trypanosomatids T. brucei, T. cruzi and Leishmania major showed that approximately 12% of their kinases are unique to trypanosomatids [63,69]. Among the protein phosphatases genes, about 40% are atypical, with no clear orthologs in other eukaryote genomes [64]. The significant differences between T. cruzi and host-cell protein kinases suggest that their specific inhibition may represent a viable therapeutic approach to control Chagas disease.…”