Protein Ser/Thr phosphatases of parasitic protozoa

Kutuzov, Mikhail A.; Андреева, А. В.

doi:10.1016/j.molbiopara.2008.06.008

Cited by 54 publications

(60 citation statements)

References 83 publications

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“…This is not a surprising regulatory mechanism, considering that the DUSP binding pockets generally lack substrate specificity. Interestingly, members of the Apicomplexa possess a unique group of pseudophosphatases with long N-terminal domains and EF-hand motifs termed "EFPPs" (64). However, a grouping of the variety of STYX domain pseudophosphatases, which have a substitution of the cysteine residue in the CX 5 R motif, has never been characterized in Plasmodium.…”

Section: Figmentioning

confidence: 99%

Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum

et al. 2013

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Intraerythrocytic development of the human malaria parasite Plasmodium falciparum appears as a continuous flow through growth and proliferation. To develop a greater understanding of the critical regulatory events, we utilized piggyBac insertional mutagenesis to randomly disrupt genes. Screening a collection of piggyBac mutants for slow growth, we isolated the attenuated parasite C9, which carried a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500. This gene encodes a protein structurally similar to a mitogen-activated protein kinase (MAPK) phosphatase, except for two notable characteristics that alter the signature motif of the dual-specificity phosphatase domain, suggesting that it may be a low-activity phosphatase or pseudophosphatase. C9 parasites demonstrated a significantly lower growth rate with delayed entry into the S/M phase of the cell cycle, which follows the stage of maximum PF3D7_1305500 expression in intact parasites. Genetic complementation with the full-length PF3D7_1305500 rescued the wild-type phenotype of C9, validating the importance of the putative protein phosphatase PF3D7_1305500 as a regulator of pre-S-phase cell cycle progression in P. falciparum. Malaria caused by Plasmodium falciparum infection is the major type of severe malaria and results in hundreds of thousands of deaths each year and hundreds of millions of clinical illnesses (1, 2). Within the blood of infected individuals, asexual forms of the intraerythrocytic parasite grow rapidly through successive cycles of growth and proliferation. In each asexual generation, active entry into erythrocytes is followed by a growth phase culminating in dynamic release of erythrocyte-invading merozoites. The Plasmodium mitotic cycle is not fully understood and differs from the well-defined models established in yeast and mammalian cells (3). Observing the exact mitotic transitions during the cycle has been difficult due to variations in processes such as chromatid segregation, nuclear division, and spindle formation (4). However, this pattern of development has been observed in other members of the Apicomplexa, such as Toxoplasma gondii and Eimeria tenella, demonstrating the importance and conservation of this process across the phylum (5, 6).In eukaryotic systems, phosphorylation cascades are critical to cellular development and depend on the coordinated activity of kinases, which are in turn modulated by the activity of phosphatases. There is growing evidence that kinases are critical regulators of cell growth and development in Plasmodium species (7-9). Plasmodium kinases, for example, have been found to be involved with the initial invasion of host cells in addition to egress and differentiation (6, 10). Additional studies have identified kinases in phosphorylation cascades of the gametocyte-ookinete-oocyst transition in the mosquito midgut (11)(12)(13)(14)(15)(16)(17). In contrast, few studies have described the phosphatases involved in these processes, which would understandably function with kinases to coregul...

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Section: Figmentioning

confidence: 99%

Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum

et al. 2013

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“…genomes identified 27 genes that are predicted to be protein phosphatases, including several prokaryote-like phosphatases (4)(5)(6). Interestingly, members of this genus of eukaryotic pathogens possess several phosphatases that cluster by sequence homology with prokaryote-like phosphatases.…”

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confidence: 99%

“…Both PfShelphs possess all of the residues that define the catalytic site of phosphoprotein phosphatase family members, suggesting that they are catalytically active (4,5,7,8). Additionally, both PfShelphs possess predicted N-terminal signal sequences, with PfShelph1 predicted to have an additional apicoplast-targeting motif (4)(5)(6). A widescale study of transcripts in P. falciparum showed that PfShelph2 is likely expressed in the invasive merozoite stage that invades host erythrocytes (12).…”

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confidence: 99%

A Bacterial Phosphatase-Like Enzyme of the Malaria Parasite Plasmodium falciparum Possesses Tyrosine Phosphatase Activity and Is Implicated in the Regulation of Band 3 Dynamics during Parasite Invasion

et al. 2013

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f Eukaryotic parasites of the genus Plasmodium cause malaria by invading and developing within host erythrocytes. Here, we demonstrate that PfShelph2, a gene product of Plasmodium falciparum that belongs to the Shewanella-like phosphatase (Shelph) subfamily, selectively hydrolyzes phosphotyrosine, as shown for other previously studied Shelph family members. In the extracellular merozoite stage, PfShelph2 localizes to vesicles that appear to be distinct from those of rhoptry, dense granule, or microneme organelles. During invasion, PfShelph2 is released from these vesicles and exported to the host erythrocyte. In vitro, PfShelph2 shows tyrosine phosphatase activity against the host erythrocyte protein Band 3, which is the most abundant tyrosine-phosphorylated species of the erythrocyte. During P. falciparum invasion, Band 3 undergoes dynamic and rapid clearance from the invasion junction within 1 to 2 s of parasite attachment to the erythrocyte. Release of Pfshelph2 occurs after clearance of Band 3 from the parasite-host cell interface and when the parasite is nearly or completely enclosed in the nascent vacuole. We propose a model in which the phosphatase modifies Band 3 in time to restore its interaction with the cytoskeleton and thus reestablishes the erythrocyte cytoskeletal network at the end of the invasion process.

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“…6,7,17 Two such SLP phosphatase containing protozoa are Trypanosoma and Plasmodium, each responsible for African sleeping sickness and malaria respectively. Interestingly, these protozoa are also known to possess a vestigial plastid (chloroplast remnant) called an apicoplast as a result of their evolution from early photosynthetic, chloroplast containing eukaryotes.…”

Section: Slp Phosphatases Identified In Human Pathogensmentioning

confidence: 99%

“…6,7,17,20 Furthermore, the complete conservation and lack of genetic redundancy of SLP phosphatases in plants may also render them targets for rational agricultural crop engineering efforts. 7 However, despite these unique traits and recent speculation as to the possible biological function(s) of the SLP phosphatases, 20 significantly more work, in a number of organismal models, will be required to completely understand the role(s) of the SLP phosphatases before any engineering efforts can be undertaken.…”

Section: Drugs and Crops: Slp Phosphatases May Representmentioning

confidence: 99%

Okadaic acid and microcystin insensitive PPP-family phosphatases may represent novel biotechnology targets

Uhrig

Moorhead²

2011

Plant Signaling & Behavior

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R eversible protein phosphorylation is of central importance to the proper cellular functioning of all living organisms. Catalyzed by the opposing reactions of protein kinases and phosphatases, dysfunction in reversible protein phosphorylation can result in a wide variety of cellular aberrations. In eukaryotic organisms there exists four classes of protein phosphatases, of which the PPP-family protein phosphatases have documented susceptibility to a range of protein and small molecule inhibitors. These inhibitors have been of great importance to the biochemical characterization of PPP-family protein phosphatases since their discovery, but also maintain in natura biological significance with their endogenous regulatory properties (protein inhibitors) and toxicity (small molecule inhibitors). Recently, two unique PPP-family protein phosphatases, named the Shewanella-like protein phosphatases (SLP phosphatases), from Arabidopsis thaliana were characterized and found to be phylogenetically similar to the PPP-family protein phosphatases protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), while completely lacking sensitivity to the classic PPP-family phosphatase small molecule inhibitors okadaic acid and microcystin-LR. SLP phosphatases were also found to be absent in metazoans, but present in a wide range of bacteria, fungi and protozoa responsible for human disease. The unique biochemical properties and evolutionary heritage of SLP phosphatases suggests they could not only be potential biotechnology targets for agriculture, but may also prove to be

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Protein Ser/Thr phosphatases of parasitic protozoa

Cited by 54 publications

References 83 publications

Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum

Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum

A Bacterial Phosphatase-Like Enzyme of the Malaria Parasite Plasmodium falciparum Possesses Tyrosine Phosphatase Activity and Is Implicated in the Regulation of Band 3 Dynamics during Parasite Invasion

Okadaic acid and microcystin insensitive PPP-family phosphatases may represent novel biotechnology targets

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