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The TriTryp phosphatome: analysis of the protein phosphatase catalytic domains.

Brenchley R, Tariq H, McElhinney H, Szöor B, Huxley-Jones J, Stevens R, Matthews K, Tabernero L - BMC Genomics (2007)

Bottom Line: The prevalence of these neglected diseases results from a combination of poverty, inadequate prevention and difficult treatment.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculty of Life Sciences, Michael Smith, University of Manchester, M13 9PT, UK. Rachel.Brenchley@postgrad.manchester.ac.uk

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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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).
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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).

Mentions: There are clearly identifiable clades in the PPP phylogenetic tree for the PP1, PP2A, PP2B, PP4, PP5 and PPEF phosphatases and these groups are well supported statistically (Figure 8).


The TriTryp phosphatome: analysis of the protein phosphatase catalytic domains.

Brenchley R, Tariq H, McElhinney H, Szöor B, Huxley-Jones J, Stevens R, Matthews K, Tabernero L - BMC Genomics (2007)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2175518&req=5

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).
Mentions: There are clearly identifiable clades in the PPP phylogenetic tree for the PP1, PP2A, PP2B, PP4, PP5 and PPEF phosphatases and these groups are well supported statistically (Figure 8).

Bottom Line: The prevalence of these neglected diseases results from a combination of poverty, inadequate prevention and difficult treatment.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculty of Life Sciences, Michael Smith, University of Manchester, M13 9PT, UK. Rachel.Brenchley@postgrad.manchester.ac.uk

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.

Show MeSH
Related in: MedlinePlus