Ubiquitin-Like Modifiers and Their Deconjugating Enzymes in Medically Important Parasitic Protozoa

Ponder, Elizabeth L.; Bogyo, Matthew

doi:10.1128/ec.00282-07

Cited by 59 publications

(72 citation statements)

References 50 publications

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“…In comparison, histone H4 sumoylation is associated with decreased gene expression (136). The malaria parasite genomes contain a number of protein homologues of E1, E2, and E3 and a number of proteases that might be involved in removing the Ubl modifications (118,120). In an effort to identify the proteome of PfSUMO modified proteins, Issar et al (74) identified sumoylated histone H4 from P. falciparum.…”

Section: Chromatin Modifications: Deposition Recognition and Functionsmentioning

confidence: 99%

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

2010

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Malaria is a major public health problem in many developing countries, with the malignant tertian parasite Plasmodium falciparum causing the most malaria-associated mortality. Extensive research, especially with the advancement of genomics and transfection tools, has highlighted the fundamental importance of chromatinmediated gene regulation in the developmental program of this early-branching eukaryote. The Plasmodium parasite genomes reveal the existence of both canonical and variant histones that make up the nucleosomes, as well as a full collection of conserved enzymes for chromatin remodeling and histone posttranslational modifications (PTMs). Recent studies have identified a wide array of both conserved and novel histone PTMs in P. falciparum, indicating the presence of a complex and divergent "histone code." Genome-wide analysis has begun to decipher the nucleosome landscape and histone modifications associated with the dynamic organization of chromatin structures during the parasite's life cycle. Focused studies on malaria-specific phenomena such as antigenic variation and red cell invasion pathways shed further light on the involvement of epigenetic mechanisms in these processes. Here we review our current understanding of chromatin-mediated gene regulation in malaria parasites, with specific reference to exemplar studies on antigenic variation and host cell invasion.Malaria continues to be a major cause of mortality and morbidity in tropical countries, bringing a death toll of ϳ1 million each year. Four human parasites (Plasmodium falciparum, P. vivax, P. malariae, and P. ovale) and a monkey parasite (P. knowlesi) have been found to infect humans naturally. P. falciparum causes the malignant form of malaria and is responsible for most malaria-associated human deaths. Intensified research in the past decade has greatly improved our understanding of the parasites and the disease they cause, especially with the sequencing of multiple parasite genomes. A striking finding from global microarray analyses of parasite gene expression is the tightly regulated transcription program during the parasite's life cycle, with genes expressed in a "just-in-time" manner (12, 93). Bioinformatic analysis has recognized a general conservation of the basal transcription machinery (15), but the scarcity of recognizable specific transcription factors in the parasite genome has led to speculation about the existence of a divergent transcription mechanism used by the malaria parasites (2, 25). However, this speculation may be inaccurate, as recent studies revealed the presence of the AP2 family of transcription factors (4, 35), which have undergone lineagespecific expansion in apicomplexan parasites (75). Nevertheless, the full complement of chromatin-modifying proteins encoded in apicomplexan parasite genomes underlines the significance of epigenetic mechanisms in transcription regulation (2,66,75,140). While epigenetic mechanisms are being intensively studied in model eukaryotes, only recently have they been explored in the m...

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Section: Chromatin Modifications: Deposition Recognition and Functionsmentioning

confidence: 99%

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

2010

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“…1A). Because mammalian Nedd8 is actually more similar to Ub than to PfNedd8 by sequence comparison (12), it was important to verify that PfUCHL3 reactivity toward PfNedd8 was real. To demonstrate that PfUCHL3 functions as a true deNeddylase in Plasmodium parasites, an electrophilic probe was generated in the form of a vinyl methyl ester added to the C-terminus of N-terminally FLAG tagged PfNedd8.…”

Section: Assessment Of Pfuchl3 As a P Falciparum-specific Deneddylasmentioning

confidence: 99%

Characterization and Structural Studies of the Plasmodium falciparum Ubiquitin and Nedd8 Hydrolase UCHL3

Artavanis‐Tsakonas

Weihofen

Antos

et al. 2010

Journal of Biological Chemistry

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Like their human hosts, Plasmodium falciparum parasites rely on the ubiquitin-proteasome system for survival. We previously identified PfUCHL3, a deubiquitinating enzyme, and here we characterize its activity and changes in active site architecture upon binding to ubiquitin. We find strong evidence that PfUCHL3 is essential to parasite survival. The crystal structures of both PfUCHL3 alone and in complex with the ubiquitinbased suicide substrate UbVME suggest a rather rigid active site crossover loop that likely plays a role in restricting the size of ubiquitin adduct substrates. Molecular dynamics simulations of the structures and a model of the PfUCHL3-PfNedd8 complex allowed the identification of shared key interactions of ubiquitin and PfNedd8 with PfUCHL3, explaining the dual specificity of this enzyme. Distinct differences observed in ubiquitin binding between PfUCHL3 and its human counterpart make it likely that the parasitic DUB can be selectively targeted while leaving the human enzyme unaffected.

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“…The relationship of the yeast proteases, known as Ulp1 and Ulp2 (8,9), to human SENPs will be discussed later. SENPs can also be found in simple eukaryotes (10), and occasionally in bacteria (11).…”

Section: Senps As Members Of the Clan Ce Proteasesmentioning

confidence: 99%

DeSUMOylating enzymes—SENPs

Drąg

Salvesen

2008

IUBMB Life

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SummaryModification of proteins by ubiquitin and SUMO (small ubiquitin-like modifiers) is a dynamic and reversible process. Similar to the ubiquitin pathway, where the action of deubiquitinating enzymes removes ubiquitin from ubiquitin-adducts, SUMO is also removed intact from its substrates by proteases belonging to the sentrin-specific proteases (SENPs) family. In addition to their isopeptidase activity, SENPs also execute another essential function as endopeptidases by removing the short C-terminal extension from immature SUMOs. The defining characteristics of SENPs are their predicted conserved molecular scaffold-defined as members of peptidase Clan CE, conserved catalytic mechanism, and their reported activity on SUMO or Nedd8 conjugated proteins (or the respective precursors). We discuss recent progress on the human SENPs and their substrates. IUBMBIUBMB Life, 60(11): 734-742, 2008

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Ubiquitin-Like Modifiers and Their Deconjugating Enzymes in Medically Important Parasitic Protozoa

Cited by 59 publications

References 50 publications

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

Characterization and Structural Studies of the Plasmodium falciparum Ubiquitin and Nedd8 Hydrolase UCHL3

DeSUMOylating enzymes—SENPs

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