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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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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.
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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.

Mentions: Analysis of the kinase domains in the kinatases indicates that they are likely to be enzymatically inactive, and we refer to them as pseudokinases for consistency with the previous classification. Comparison to eukaryotic protein kinases highlights the lack of residues essential for catalytic activity and substrate binding (Figure 5). For example, the glycine triad (GXGXXG) necessary for ATP binding is only present in one of the T. cruzi kinase domains, and the catalytic Asp residue in the active site HRD motif is substituted by other residues in all of the kinase domains. The first kinase domain in the kinatases also has substitutions in the magnesium-binding DFG motif. Although these pseudokinase domains might have lost the capability to phosphorylate substrates, they may still perform important regulatory roles in signalling pathways as has been reported for other pseudokinases [44]. The presence of the LRR modules strongly suggests a role in protein-protein interactions, while the addition of an active DSP domain and pseudokinase domains hints to a sophisticated regulatory function, which has not been reported in higher eukaryotes. A similar domain architecture (kinase + phosphatase) is present in other protozoan organisms such as Giardia lamblia, Tetrahymena thermophila, and Dictyostelium discoideum, indicating evolutionary conservation of a these proteins. Sequences with LRRs and DSP domains only, are also present in other protozoa: Entamoeba histolytica and Dictyostelium discoideum suggesting that this family may be also specific to protozoa. It will be interesting to further explore the functional relevance of these novel DSPs in kinetoplastid signalling.


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)

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

License
Show All Figures
getmorefigures.php?uid=PMC2175518&req=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.
Mentions: Analysis of the kinase domains in the kinatases indicates that they are likely to be enzymatically inactive, and we refer to them as pseudokinases for consistency with the previous classification. Comparison to eukaryotic protein kinases highlights the lack of residues essential for catalytic activity and substrate binding (Figure 5). For example, the glycine triad (GXGXXG) necessary for ATP binding is only present in one of the T. cruzi kinase domains, and the catalytic Asp residue in the active site HRD motif is substituted by other residues in all of the kinase domains. The first kinase domain in the kinatases also has substitutions in the magnesium-binding DFG motif. Although these pseudokinase domains might have lost the capability to phosphorylate substrates, they may still perform important regulatory roles in signalling pathways as has been reported for other pseudokinases [44]. The presence of the LRR modules strongly suggests a role in protein-protein interactions, while the addition of an active DSP domain and pseudokinase domains hints to a sophisticated regulatory function, which has not been reported in higher eukaryotes. A similar domain architecture (kinase + phosphatase) is present in other protozoan organisms such as Giardia lamblia, Tetrahymena thermophila, and Dictyostelium discoideum, indicating evolutionary conservation of a these proteins. Sequences with LRRs and DSP domains only, are also present in other protozoa: Entamoeba histolytica and Dictyostelium discoideum suggesting that this family may be also specific to protozoa. It will be interesting to further explore the functional relevance of these novel DSPs in kinetoplastid signalling.

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