The serine/threonine phosphatases of apicomplexan parasites

Abstract

The balance between phosphorylation and de-phosphorylation, which is delicately regulated by protein kinases and phosphatases, is critical for nearly all biological processes. The Apicomplexa are a large phylum which contains various parasitic protists, including human pathogens, such as Plasmodium, Toxoplasma, Cryptosporidium and Babesia species. The diverse life cycles of these parasites are highly complex and, not surprisingly, many of their key steps are exquisitely regulated by phosphorylation. Interestingly, many of the kinases and phosphatases, as well as the substrates involved in these events are unique to the parasites and therefore phosphorylation constitutes a viable target for antiparasitic intervention. Most progress on this realm has come from studies in Toxoplasma and Plasmodium of their respective kinomes and phosphoproteomes. Nonetheless, given their likely importance, phosphatases have recently become the focus of research within the apicomplexan parasites. In this review, we concentrate on serine/threonine phosphatases in apicomplexan parasites, with the focus on comprehensively identifying and naming protein phosphatases in available apicomplexan genomes, and summarizing the progress of their functional analyses in recent years.

Figure 1. The PPP family phosphatases of T. gondii, P. falciparum, B. bovis, and C. parvum

The phylogenetic tree shown was assembled based on the alignments of the catalytic domains of the PPP family phosphatase members found in the genomes of T. gondii (Tg), P. falciparum (Pf), C. parvum (Cp), and B. bovis (Bb). Protein alignment was performed with MUSCLE, and Gblocks 0.91b was used to select conserved blocks for tree-building. The phylogenetic analysis was performed using PHYML 3.0 with a maximum likelihood method under the LG model of amino acids substitution. Branch support values were estimated by Approximate Likelihood-Ratio Test (aLRT). The final tree was condensed with a cut-off value 50%. The branches of each subfamily are displayed in an individual color. The domain architecture of each phosphatase is shown to the right of its branch. Domains shown include PPPc, PPP catalytic domain; Kelch, kelch domain; EF-hand, EF-hand motif; BBH, CNB-binding helix; CBD, Ca²⁺-calmodulin-binding motif; AI, autoinhibitory sequence; TPR, Tetratricopeptide repeat domain; IQ, Calmodulin-binding motif; CAP_GLY, Cytoskeleton-associated protein glycine-rich domain. The alignments of the core catalytic motif sequences are displayed to the right of each corresponding domain architecture. The relative location and consensus sequences of each core catalytic motif are shown underneath the alignments. The residues shown in red or green are those contribute to metal coordination or phosphate binding.

Figure 2. The PPM family phosphatases of T. gondii, P. falciparum, B. bovis, and C. parvum.

The phylogenetic tree was constructed based on the alignments of the PP2C catalytic domains of the PPM family members from the four apicomplexans and the 20 PPM members (18 PP2Cs and 2 PDPs) of human and 8 (7 PP2Cs and 1 PDP) of budding yeast. Alignments and tree assembly were performed as in figure 1. Domain architecture and alignments of the core catalytic motif sequences are also shown as in figure 1. Domains include PP2Cc, PP2C catalytic domain; SP, Signal peptide; Coiled coil, Coiled coil motif; TM, Transmembrane domain; LRR, Leucine-rich repeats; PH, Pleckstrin homology domain. The PPM family phosphatase are clustered into 10 groups, each annotated with a different color and a group name from I to X.

Figure 3. The FCP/SCP family phosphatases of T. gondii, P. falciparum, B. bovis, and C. parvum

The phylogenetic tree shown was built based on the alignments of the catalytic domains of the FCP/SCP family phosphatases from humans, budding yeast, and the four apicomplexans studied. Alignments and tree assembly were done as for figure 1. The FCP/SCP family phosphatase are clustered into five groups, each annotated with a different color. Domain architecture and alignments of the core catalytic motif sequences are shown as in figure 1. Domains include CPDc, CTD-like phosphatase catalytic domain; TM, Transmembrane domain; BRCT, Breast cancer carboxy-terminal domain; UBQ, Ubiquitin homologue domain.