title: Characterization of the 26S proteasome network in Plasmodium falciparum.
abstract: In eukaryotic cells, the ubiquitin-proteasome system as a key regulator of protein quality control is an excellent drug target. We therefore aimed to analyze the 26S proteasome complex in the malaria parasite Plasmodium falciparum, which still threatens almost half of the world's population. First, we established an affinity purification protocol allowing for the isolation of functional 26S proteasome complexes from the parasite. Subunit composition of the proteasome and component stoichiometry were studied and physiologic interacting partners were identified via in situ protein crosslinking. Furthermore, intrinsic ubiquitin receptors of the plasmodial proteasome were determined and their roles in proteasomal substrate recognition were analyzed. Notably, PfUSP14 was characterized as a proteasome-associated deubiquitinase resulting in the concept that targeting proteasomal deubiquitinating activity in P. falciparum may represent a promising antimalarial strategy. The data provide insights into a profound network orchestrated by the plasmodial proteasome and identified novel drug target candidates in the ubiquitin-proteasome system.
authors.affiliation: Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Giessen, Germany.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California.
authors.forename: Claire
authors.initials: C
authors.lastname: Delahunty
authors.affiliation: Max-Planck Institute for Medical Research, Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Fritz-Wolf
authors.affiliation: Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Giessen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rahlfs
authors.affiliation: Department of Chemistry, Western Connecticut State University, Danbury, Connecticut.
authors.forename: Judith
authors.initials: J
authors.lastname: Helena Prieto
authors.affiliation: Max-Planck Institute for Medical Research, Heidelberg, Germany.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Giessen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D002846:Chromatography, Affinity; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005557:Formaldehyde / Q000494:pharmacology; D006801:Humans; D046912:Multiprotein Complexes / Q000302:isolation & purification / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000302:isolation & purification / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D040901:Proteomics; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D040681:Structural Homology, Protein; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism
chemical_list: D000962:Antimalarials; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D025801:Ubiquitin; D005557:Formaldehyde; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease