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Phylogenetic Analysis of Protein Phosphatases of the Malaria Parasite Plasmodium falciparum

Phylogenetic Analysis of Protein Phosphatases of the Malaria Parasite Plasmodium falciparum Jonathan M. Wilkes & Christian Doerig. Introduction. Malaria is a major source of morbidity and mortality in the developing world (>1m deaths per year).

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Phylogenetic Analysis of Protein Phosphatases of the Malaria Parasite Plasmodium falciparum

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  1. Phylogenetic Analysis of Protein Phosphatases of the Malaria Parasite Plasmodium falciparum Jonathan M. Wilkes & Christian Doerig

  2. Introduction • Malaria is a major source of morbidity and mortality in the developing world (>1m deaths per year). • The genome of Plasmodium falciparum, the causative agent, has been sequenced and annotated. • Protein phosphorylation (kinases) and dephosphorylation (phosphatases) on serine, threonine and tyrosine residues is a ubiquitous regulatory mechanism and potential drug target. • The ‘kinome’ of P. falciparum contains a relatively small number of proteins: either Ser/Thr or Dual Specificity (Ser/Thr/Tyr) but no Tyrosine kinases. • The genomes of P. falciparum and a representative range of other eukaryotes searched with Hidden Markov Models for protein phosphatase catalytic domains. • Sequences from each superfamily/clan (Metallophosphatase, PP2c and PTP) subjected to multiple sequence alignment and phylogenetic analysis (NeighbourNet on SplitsTree4)

  3. Calcineurin like metallophosphatase family

  4. PPM type SpoIIE like PP2c (Ser/Thr phosphatase) superfamily

  5. Tyrosine Phosphatase Receptor type PTEN Non-receptor type Type IVA mRNA capping Tyrosine phosphatase type 2 PTP-KIS Dual specificity phosphatase Protein Tyrosine Phosphatase Family (PTP)

  6. Conclusions • P. falciparum has the smallest ‘phosphatome’ of the organisms analysed. • Within the PPP phosphatases there is exactly one protein of each subtype (‘bottleneck’ event selecting minimal number of PPPs?). • P. falciparum possesses two bacterial type PPP (shelphs) and one ‘classic’ PPP (BSU) without human homologues. • Most P. falciparum PP2c sequences are members of a distinct clade with no human homologues. (Duplication and selection of ancestral protein following a ‘bottleneck’ event?). • P. falciparum has no tyrosine phosphatase type sequences, and has two closely related DSPc sequences (consistent with ‘kinome’). A PTP type IVa with a prenylation signal sequence (membrane targetted) is also found. • Phylogenetic comparison of the P. falciparum ‘phosphatome’ with other representative organisms indicates a number of possible targets for pharmaceutical intervention and suggest a complex evolutionary history for this organism.

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