The Multifaceted Role of Protein Phosphatase 1 in Plasmodium

Abstract

Protein Phosphatase type 1 (PP1) forms a wide range of Ser/Thr specific phosphatase holoenzymes which contain one catalytic subunit (PP1c), present in all eukaryotic cells, associated with variable subunits known as regulatory proteins. It has recently been shown that regulators take a leading role in the organization and the control of PP1 functions. Many studies have addressed the role of these regulators in diverse organisms including humans and investigated their link to diseases. In this review we summarize recent advances on PP1c in Plasmodium, its interactome and regulators. As a proof of concept, peptides interfering with the regulator binding capacity of PP1c were shown to inhibit the growth of P. falciparum, suggesting their potential as drug precursors.

Protein Phosphatase 1 regulates atypical mitotic and meiotic division inPlasmodiumsexual stages

“…Other biochemical studies in Plasmodium have identified numerous PP1-interacting partners (PIPs) that are structurally conserved and regulate PP1 activity, including LRR1 (a human SDS22 orthologue), Inhibitor 2 and Inhibitor 3. Other PIPs including eif2β, and GEXP15 have also been identified 9, 28, 30, 31 . However, little is known regarding how PP1 is involved in regulating mitosis and meiosis in the absence of CDC14 and CDC25.…”

“…Other biochemical studies in Plasmodium have identified numerous PP1-interacting partners (PIPs) that are structurally conserved and regulate PP1 activity, including LRR1 (a human SDS22 orthologue), Inhibitor 2 and Inhibitor 3. Other PIPs including eif2β, and GEXP15 have also been identified 9, 24, 31, 32, 33 . Synthetic peptides containing the RVxF motif of Inhibitor 2 and Inhibitor 3, and the LRR and the LRR cap motif of Pf LRR1 significantly reduce P. falciparum growth in vitro 34, 35 and regulate Pf PP1 phosphatase activity 35, 36, 37 .…”

“…Previous studies determined that P. falciparum PP1 functionally complements the Saccharomyces cerevisiae glc7 (PP1) homologue 24 , and subsequent phylogenetic analyses revealed that homologues of the phosphatases CDC14 and CDC25 are absent from Plasmodium 23 . Genetic screens and inhibitor studies have shown that PP1 is essential for asexual blood stage development 23, 25, 26, 27 (also reviewed 28 ), in particular for parasite egress from the host erythrocyte 29 . Most studies in Plasmodium have been focused on these asexual blood stages of parasite proliferation, and very little is known about the importance of PP1 for transmission stages within the mosquito vector.…”

“…In Plasmodium , the causative organism of malaria, there is a single PP1 orthologue, which is expressed throughout the parasite’s complex life-cycle 22 and located in both nucleus and cytoplasm 23 . P. falciparum PP1 ( Pf PP1) shares 80% identity with human PP1c, and likely has a conserved tertiary and secondary structure containing 9 α-helices and 11 β-strands 24 . However, Pf PP1 lacks part of the 18 amino-acid motif at the C-terminus of human PP1, which contains a threonine residue (Thr320) that is phosphorylated by CDC2 kinase 25 and dynamically regulates entry into mitosis 24 .…”

“…P. falciparum PP1 ( Pf PP1) shares 80% identity with human PP1c, and likely has a conserved tertiary and secondary structure containing 9 α-helices and 11 β-strands 24 . However, Pf PP1 lacks part of the 18 amino-acid motif at the C-terminus of human PP1, which contains a threonine residue (Thr320) that is phosphorylated by CDC2 kinase 25 and dynamically regulates entry into mitosis 24 . Previous studies determined that P. falciparum PP1 functionally complements the Saccharomyces cerevisiae glc7 (PP1) homologue 26 , and subsequent phylogenetic analyses revealed that homologues of the phosphatases CDC14 and CDC25 are absent from Plasmodium 23 .…”