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. 2007 Nov 26:8:434.
doi: 10.1186/1471-2164-8-434.

The TriTryp phosphatome: analysis of the protein phosphatase catalytic domains

Affiliations

The TriTryp phosphatome: analysis of the protein phosphatase catalytic domains

Rachel Brenchley et al. BMC Genomics. .

Abstract

Background: The 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.

Results: An 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.

Conclusion: The 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.

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Figures

Figure 1
Figure 1
Comparison of the protein phosphatase complement in different genomes. Pie charts show the distribution of phosphatase catalytic domain genes in the different families: S/T Phosphatases, Protein tyrosine phosphatases, Dual-specificity phosphatases and PTEN/MTM lipid phosphatases. Phosphatase complements are shown for T. cruzi, T. brucei, L. major, in comparison with those for the Human [24, 26, 29, 128], S. cerevisiae [129, 130] and A. thaliana [76, 131] genomes. ACR2/cdc25-like are included in the DSP group.
Figure 2
Figure 2
Domain organisation of the T. cruzi, T. brucei and L. major phosphatases. Domains are colour-coded according to the type of domain and grouped within phosphatase subfamilies. PTP, protein tyrosine phosphatase; DSP, dual-specificity phosphatase (crossed means pseudophosphatase); kinase, protein kinase domain (crossed means pseudokinase); TPR, Tetratricopeptide repeat; LRR, Leucine rich repeat; CaLB, Calcium lipid binding; GRAM, glucosyltransferases, Rab-like GTPases activators and myotubularins domain (plasma membrane protein-binding domain); FYVE, Fab1p/YOTB, Vac1p/EEA1 (PI3P binding domain); EF-hand, calcium binding domain; S/T phosphatase, serine/threonine phosphatase catalytic domain; FCP, CTD protein phosphatase. Note that many InterPro domains are variations representing the same biological function and sometimes they overlap. Only one domain is represented for these regions in this figure. Numbers of each domain type are listed for the kinetoplastids and '-' shows where one of the parasites lacks a particular architecture. ACR2/cdc25-like are included in the DSP group.
Figure 3
Figure 3
Phylogram of TriTryp PTPs. The phylogram of PTP catalytic domains includes TriTryp sequences and human, S. cerevisiae and A. thaliana as markers. Phosphatase domains are indicated by systematic gene IDs. Sequences are colour-coded by organism: blue for T. cruzi (Tc), T. brucei (Tb) and L. major (LmjF); red for human (Hs); brown for S. cerevisiae (Sc) and green for A. thaliana (At). Protein names replace Swiss-Prot IDs for some human, yeast and plant sequences. Results of the four phylogenetic methods are shown: bootstrap values > 70 are black for Neighbour-Joining, brown for Bayesian and purple for Maximum Parsimony. Asterisks (*) show Maximum Likelihood support.
Figure 4
Figure 4
Radial phylogenetic tree of TriTryp DSPs and PTPs. Neighbour joining tree showing T. cruzi (Tc), T. brucei (Tb) and L. major (LmjF) sequences. Sequence IDs are colour-coded according to groupings as labelled in the figure. Bootstrapping values > 70 are shown as dots on the branches. T. cruzi sequence IDs are truncated to the unique part, so the invariant 00.10470535 has been removed.
Figure 5
Figure 5
Conservation of protein kinase motifs in the kinetoplastid 'kinatases'. The 11 subdomains of eukaryotic protein kinases are represented as blocks, with essential conserved residues for catalysis marked above. Analysis of the both kinase domains from the three kinatases is shown underneath. Fully conserved motifs are boxed in black and conserved residues from partially conserved regions are in bold type.
Figure 6
Figure 6
Phylogram of TriTryp MKPs. The phylogram of MKPs shows DSP catalytic domains from TriTryp sequences and human, S. cerevisiae and A. thaliana as markers. Phosphatase domains are indicated by systematic gene IDs. Sequences are colour-coded by organism: blue for T. cruzi (Tc), T. brucei (Tb) and L. major (LmjF); red for human (Hs); brown for S. cerevisiae (Sc) and green for A. thaliana (At). Protein names replace Swiss-Prot IDs for some human, yeast and plant sequences. The results of the four phylogenetic methods are shown: bootstrap values > 70 are black for Neighbour-Joining, brown for Bayesian and purple for Maximum Parsimony. Asterisks (*) show Maximum Likelihood support.
Figure 7
Figure 7
Phylogram of TriTryp lipid phosphatases. The phylogram of lipid phosphatases shows DSP/lipid catalytic domains from TriTryp sequences and human, S. cerevisiae and A. thaliana as markers. Phosphatase domains are indicated by systematic gene IDs. Sequences are colour-coded by organism: blue for T. cruzi (Tc), T. brucei (Tb) and L. major (LmjF); red for human (Hs); brown for S. cerevisiae (Sc) and green for A. thaliana (At). Protein names replace Swiss-Prot IDs for some human, yeast and plant sequences. The results of the four phylogenetic methods are shown: bootstrap values > 70 are black for Neighbour-Joining, brown for Bayesian and purple for Maximum Parsimony. Asterisks (*) show Maximum Likelihood support.
Figure 8
Figure 8
Phylogram of the PPP subfamily of serine/threonine phosphatases. Included are TriTryp PPP catalytic domains and those from human, S. cerevisiae and A. thaliana. Phosphatase domains are indicated by systematic gene IDs. Sequences are colour-coded by organism: blue for T. cruzi (Tc), T. brucei (Tb) and L. major (LmjF); red for human (Hs); brown for S. cerevisiae (Sc) and green for A. thaliana (At). Protein names replace Swiss-Prot IDs for some human, yeast and plant sequences and systematic IDs for the parasites. Results of the four phylogenetic methods are shown: bootstrap values > 70 are black for Neighbour-Joining, brown for Bayesian and purple for Maximum Parsimony. Asterisks (*) show Maximum Likelihood support. The symbol '+' marks kinetoplastid sequences with catalytic mutations (listed in Additional file 8).
Figure 9
Figure 9
Phylogram of the PPM type of serine/threonine phosphatases. This phylogram includes PPM catalytic domains from human, S. cerevisiae and A. thaliana. Phosphatase domains are indicated by systematic gene IDs. Sequences are colour-coded by organism: blue for T. cruzi (Tc), T. brucei (Tb) and L. major (LmjF); red for human (Hs); brown for S. cerevisiae (Sc) and green for A. thaliana (At). Most sequence IDs are from the Swiss-Prot database but there are also NCBI database accession numbers used (beginning 'NP'). Results of the four phylogenetic methods are shown: bootstrap values > 70 are black for Neighbour-Joining, brown for Bayesian and purple for Maximum Parsimony. Asterisks (*) show Maximum Likelihood support. Dashed lines show phylogenetic relationships as indicated in an initial tree from an ungapped alignment. Each clade was analysed separately to obtain robust phylogenetic analysis and these were then combined to show the whole PPM family.

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