Download Wilkes

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).
• 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)
Calcineurin like metallophosphatase family
PPM
type
SpoIIE like
PP2c (Ser/Thr phosphatase) superfamily
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)
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.