Hyper-expansion of asparagines correlates with an abundance of proteins with prion-like domains in Plasmodium falciparum

Singh, Gajinder Pal; Chandra, Beeram Ravi; Bhattacharya, Arindam; Akhouri, Reetesh Raj; Singh, Saurabh Kumar; Sharma, Amit

doi:10.1016/j.molbiopara.2004.05.016

Cited by 79 publications

(89 citation statements)

References 39 publications

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“…Further, the occurrence of acidic residue homorepeats in PfNap proteins seems to be functionally relevant to the histone binding dynamics and in this case may not reflect the amino acid composition peculiarities of P. falciparum proteins (31). In summary, our data suggest a distinct and non-overlapping functional roles for P. falciparum NapS and NapL proteins in chromatin assembly and histone transport, respectively.…”

Section: Discussionmentioning

confidence: 69%

The Two Plasmodium falciparum Nucleosome Assembly Proteins Play Distinct Roles in Histone Transport and Chromatin Assembly

Navadgi

Chandra

Mishra

et al. 2006

Journal of Biological Chemistry

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The malarial parasite Plasmodium falciparum has two nucleosome assembly proteins, PfNapS and PfNapL (Chandra, B. R., Olivieri, A., Silvestrini, F., Alano, P., and Sharma, A. (2005) Mol. Biochem. Parasitol. 142, 237-247). We show that both PfNapS and PfNapL interact with histone oligomers but only PfNapS is able to deposit histones onto DNA. This property of PfNapS is divalent cation-dependent and ATP-independent. Deletion of the terminal subdomains of PfNapS abolishes its nucleosome assembly capabilities, but the truncated protein retains its ability to bind histones. Both PfNapS and PfNapL show binding to the linker histone H1 suggesting their probable role in extraction of H1 from chromatin fibers. Our data suggests distinct sites of interaction for H1 versus H3/H4 on PfNapS. We show that PfNapS and PfNapL are phosphorylated both in vivo and in vitro by casein kinase-II, and this modification is specifically inhibited by heparin. Circular dichroism, fluorescence spectroscopy, and chymotrypsin fingerprinting data together suggest that PfNapL may undergo very small and subtle structural changes upon phosphorylation. Specifically, phosphorylation of PfNapL increases its affinity 3-fold for core histones H3, H4, and for the linker histone H1. Finally, we demonstrate that PfNapS is able to extract histones from both phosphorylated and unphosphorylated PfNapL, potentially for histone deposition onto DNA. Based on these results, we suggest that the P. falciparum NapL is involved in the nucleocytoplasmic relay of histones, whereas PfNapS is likely to be an integral part of the chromatin assembly motors in the parasite nucleus.

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Section: Discussionmentioning

confidence: 69%

The Two Plasmodium falciparum Nucleosome Assembly Proteins Play Distinct Roles in Histone Transport and Chromatin Assembly

Navadgi

Chandra

Mishra

et al. 2006

Journal of Biological Chemistry

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“…Many open reading frames in P. falciparum contain several asparagines and lysine and serine-rich repeat regions (26). The heterologous expression of Plasmodium proteins is extremely difficult due to the ϳ80% AT richness of the Plasmodium genome and different codon usage in Plasmodium.…”

Section: Resultsmentioning

confidence: 99%

Functional Dissection of the Catalytic Carboxyl-Terminal Domain of Origin Recognition Complex Subunit 1 (PfORC1) of the Human Malaria Parasite Plasmodium falciparum

et al. 2009

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Origin recognition complex subunit 1 (ORC1) is essential for DNA replication in eukaryotes. The deadly human malaria parasite Plasmodium falciparum contains an ORC1/CDC6 homolog with several interesting domains at the catalytic carboxyl-terminal region that include a putative nucleoside triphosphate-binding and hydrolysis domain, a putative PCNA-interacting-protein (PIP) motif, and an extreme C-terminal region that shows poor homology with other ORC1 homologs. Due to the unavailability of a dependable inducible gene expression system, it is difficult to study the structure and function of essential genes in Plasmodium. Using a genetic yeast complementation system and biochemical experiments, here we show that the putative PIP domain in ORC1 that facilitates in vitro physical interaction with PCNA is functional in both yeast (Saccharomyces cerevisiae) and Plasmodium in vivo, confirming its essential biological role in eukaryotes. Furthermore, despite having less sequence homology, the extreme C-terminal region can be swapped between S. cerevisiae and P. falciparum and it binds to DNA directly, suggesting a conserved role of this region in DNA replication. These results not only provide us a useful system to study the function of the essential genes in Plasmodium, they help us to identify the previously undiscovered unique features of replication proteins in general.Origin recognition complex subunit 1 (ORC1), the largest subunit among the ORC components is essential for DNA replication initiation in eukaryotes. ORC1 has a regulatory function in DNA replication since it comes on and off chromatin during cell cycle. Human ORC binds to chromatin during G 1 phase of the cell cycle, followed by degradation of ORC1 by a ubiquitin-mediated pathway. ORC1 reappears during M phase, and it binds to DNA at the onset of G 1 phase (21). In mammalian cells, monoubiquitination and phosphorylation may also lead to the subcellular localization of ORC1 to control DNA replication (24). In the case of Xenopus laevis, ORC1 is bound to chromatin during early interphase but it is destabilized later with the loading of MCM proteins on chromatin (23). While in Drosophila melanogaster, the level of ORC1 is developmentally regulated (2), the murine ORC1 binds to specific locus in the ribosomal RNA in a cell-cycledependent manner (29). Interestingly, in the yeast Saccharomyces cerevisiae, although ORC is tightly bound to chromatin throughout the cell cycle, another pre-replication complex (pre-RC) protein, CDC6, comes on and off chromatin, ensuring the control of DNA replication during cell cycle (7,22). The role of S. cerevisiae ORC1 (ScORC1) in ORC-DNA binding and modulating ScORC function has been described recently using highresolution electron microscopy of ScORC (5).ORC1 proteins consist of two highly conserved domains: the N-terminal regulatory domain that contains the bromo-adjacent homology domain and the C-terminal catalytic domain that contains the AAA ϩ ATPase domain. The bromo-adjacent homology domain is involved in the regulati...

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“…PfCK2␣ contains the major motifs conserved across Within the alveolates, Plasmodium yoelii yoelii (125 residues) and Plasmodium vivax (157 residues) also have long extensions, but the extension of P. falciparum is the longest known. Homorepeat-containing proteins make up 35.7% of the proteome of P. falciparum, although the majority of these homorepeats are asparagines and lysines (48), unlike the polymers of acidic residues present in PfCK2␤2. One hypothesis for the function of this extension is the downregulation of the alpha subunit.…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of Protein Kinase CK2 of the Human Malaria Parasite Plasmodium falciparum

et al. 2009

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Protein kinase CK2 (casein kinase 2) is a eukaryotic serine/threonine protein kinase with multiple substrates and roles in diverse cellular processes, including differentiation, proliferation, and translation. The mammalian holoenzyme consists of two catalytic alpha or alpha subunits and two regulatory beta subunits. We report the identification and characterization of a Plasmodium falciparum CK2␣ orthologue, PfCK2␣, and two PfCK2␤ orthologues, PfCK2␤1 and PfCK2␤2. Recombinant PfCK2␣ possesses protein kinase activity, exhibits similar substrate and cosubstrate preferences to those of CK2␣ subunits from other organisms, and interacts with both of the PfCK2␤ subunits in vitro. Gene disruption experiments show that the presence of PfCK2␣ is crucial to asexual blood stage parasites and thereby validate the enzyme as a possible drug target. PfCK2␣ is amenable to inhibitor screening, and we report differential susceptibility between the human and P. falciparum CK2␣ enzymes to a small molecule inhibitor. Taken together, our data identify PfCK2␣ as a potential target for antimalarial chemotherapeutic intervention.

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Hyper-expansion of asparagines correlates with an abundance of proteins with prion-like domains in Plasmodium falciparum

Cited by 79 publications

References 39 publications

The Two Plasmodium falciparum Nucleosome Assembly Proteins Play Distinct Roles in Histone Transport and Chromatin Assembly

The Two Plasmodium falciparum Nucleosome Assembly Proteins Play Distinct Roles in Histone Transport and Chromatin Assembly

Functional Dissection of the Catalytic Carboxyl-Terminal Domain of Origin Recognition Complex Subunit 1 (PfORC1) of the Human Malaria Parasite Plasmodium falciparum

Functional Analysis of Protein Kinase CK2 of the Human Malaria Parasite Plasmodium falciparum

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