title: Characterization and Structural Insights into Selective E1-E2 Interactions in the Human and Plasmodium falciparum SUMO Conjugation Systems.
abstract: Protein modification by small ubiquitin-related modifiers (SUMOs) is essential and conserved in the malaria parasite, Plasmodium falciparum. We have previously shown that interactions between the SUMO E1-activating and E2-conjugating enzyme in P. falciparum are distinct compared with human, suggesting a potential target for development of parasite-specific inhibitors of SUMOylation. The parasite asexual trophozoite stage is susceptible to iron-induced oxidative stress and is subsequently a target for many of the current anti-malarial drugs. Here, we provide evidence that SUMOylation plays a role in the parasite response to oxidative stress during red blood cell stages, indicative of a protective role seen in other organisms. Using x-ray crystallography, we solved the structure of the human SUMO E1 ubiquitin fold domain in complex with the E2, Ubc9. The interface defined in this structure guided in silico modeling, mutagenesis, and in vitro biochemical studies of the P. falciparum SUMO E1 and E2 enzymes, resulting in the identification of surface residues that explain species-specific interactions. Our findings suggest that parasite-specific inhibitors of SUMOylation could be developed and used in combination therapies with drugs that induce oxidative stress.
authors.affiliation: From the Department of Biochemistry and Molecular Biology and.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Reiter
authors.affiliation: From the Department of Biochemistry and Molecular Biology and.
authors.forename: Anita
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: From the Department of Biochemistry and Molecular Biology and.
authors.forename: Xue
authors.initials: X
authors.lastname: Xia
authors.affiliation: From the Department of Biochemistry and Molecular Biology and the Johns Hopkins Malaria Research Institute, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Boucher
authors.affiliation: From the Department of Biochemistry and Molecular Biology and the Johns Hopkins Malaria Research Institute, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bosch
authors.affiliation: From the Department of Biochemistry and Molecular Biology and mmatuni1@jhu.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Matunis
mesh_terms: D006801:Humans; D008958:Models, Molecular; D018384:Oxidative Stress / Q000502:physiology; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D058207:Sumoylation / Q000502:physiology; D053058:Trophozoites / Q000737:chemistry / Q000201:enzymology; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D015800:Protozoan Proteins; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: crystallography; malaria; oxidative stress; plasmodium; small ubiquitin-like modifier (SUMO); ubiquitin fold domain (Ufd); ubiquitin-conjugating enzyme (E2 enzyme)