Characterization of a PRL protein tyrosine phosphatase from Plasmodium falciparum☆

Pendyala, Prakash Rao; Ayong, Lawrence; Eatrides, Jennifer; Schreiber, Melissa; Pham, Connie; Chakrabarti, Ratna; Fidock, David A.; Allen, Charles M.; Chakrabarti, Debopam

doi:10.1016/j.molbiopara.2007.11.006

Cited by 37 publications

(46 citation statements)

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“…A detailed understanding of invasion requires extensive characterization of the parasite and host factors involved, including evaluating the activity and subcellular localization of the putative kinases and phosphatases identified in the genomes of these organisms. While a number of malaria parasite-derived kinases (34,35) and phosphatases (4,6,36,37) have been identified, the activities and functions of most of the kinases and phosphatases of Plasmodium sp. parasites remain to be fully delineated.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…It is also noteworthy to mention that tyrosinespecific phosphatases have been identified in the parasite [37,38]. Therefore, cellular tyrosine phosphorylation in P. falciparum may be modulated through the cooperative function of these phosphatases and the dual-specificity kinases.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum possesses a unique dual-specificity serine/threonine and tyrosine kinase, Pfnek3

Low

Chua

Sim

2011

Cell. Mol. Life Sci.

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Despite the absence of classical tyrosine kinases encrypted in the kinome of Plasmodium falciparum, biochemical analyses have detected significant tyrosine phosphorylation in its cell lysates. Supporting such phosphorylation is critical for parasite development. These observations have thus raised queries regarding the plasmodial enzymes accountable for tyrosine kinase activities in vivo. In the current investigation, immunoblot analysis intriguingly demonstrated that Pfnek3, a plasmodial mitogen-activated protein kinase kinase (MAPKK), displayed both serine/threonine and tyrosine kinase activities in autophosphorylation reactions as well as in phosphorylation of the exogenous myelin basic protein substrate. The results obtained strongly support Pfnek3 as a novel dual-specificity kinase of the malarial parasite, even though it displays a HGDLKSTN motif in the catalytic loop that resembles the consensus HRDLKxxN signature found in the serine/threonine kinases. Notably, its serine/threonine and tyrosine kinase activities were found to be distinctly influenced by Mg(2+) and Mn(2+) cofactors. Further probing into the regulatory mechanism of Pfnek3 also revealed tyrosine phosphorylation to be a crucial factor that stimulates its kinase activity. Through biocomputational analyses and functional assays, tyrosine residues Y117, Y122, Y172, and Y238 were proposed as phosphorylation sites essential for mediating the catalytic activities of Pfnek3. The discovery of Pfnek3's dual role in phosphorylation marks its importance in closing the loop for cellular regulation in P. falciparum, which remains elusive to date.

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“…The SNARE protein Ykt6.1 of P. falciparum (PfYkt6.1) has been shown to be a farnesyltransferase substrate in vitro, and its localization is disrupted when lacking a CaaX motif, suggesting it is also a prenylation target in vivo (73). Similarly, the P. falciparum tyrosine phosphatase PfPRL is a substrate for farnesylation in vitro (74).…”

Section: Sesquiterpenes and Diterpenesmentioning

confidence: 99%

Isoprenoid Biosynthesis in Plasmodium falciparum

2014

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bMalaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research.

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Characterization of a PRL protein tyrosine phosphatase from Plasmodium falciparum☆

Cited by 37 publications

References 50 publications

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

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

Plasmodium falciparum possesses a unique dual-specificity serine/threonine and tyrosine kinase, Pfnek3

Isoprenoid Biosynthesis in Plasmodium falciparum

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