title: The Prenylated Proteome ofPlasmodium falciparumReveals Pathogen-specific Prenylation Activity and Drug Mechanism-of-action.
abstract: Plasmodiumparasites contain several unique membrane compartments in which prenylated proteins may play important roles in pathogenesis. Protein prenylation has also been proposed as an antimalarial drug target because farnesyltransferase inhibitors cause potent growth inhibition of blood-stagePlasmodiumHowever, the specific prenylated proteins that mediate antimalarial activity have yet to be identified. Given the potential for new parasite biology and elucidating drug mechanism-of-action, we performed a large-scale identification of the prenylated proteome in blood-stageP. falciparumparasites using an alkyne-labeled prenyl analog to specifically enrich parasite prenylated proteins. Twenty high-confidence candidates were identified, including several examples of pathogen-specific prenylation activity. One unique parasite prenylated protein was FYVE-containing coiled-coil protein (FCP), which is only conserved inPlasmodiumand related Apicomplexan parasites and localizes to the parasite food vacuole. Targeting of FCP to this parasite-specific compartment was dependent on prenylation of its CaaX motif, as mutation of the prenylation site caused cytosolic mislocalization. We also showed thatPfRab5b, which lacksC-terminal cysteines that are the only known site of Rab GTPase modification, is prenylated. Finally, we show that the THQ class of farnesyltransferase inhibitors abolishes FCP prenylation and causes its mislocalization, providing the first demonstration of a specific prenylated protein disrupted by antimalarial farnesyl transferase inhibitors. Altogether, these findings identify prenylated proteins that reveal unique parasite biology and are useful for evaluating prenyltransferase inhibitors for antimalarial drug development.
authors.affiliation: From the ‡Department of Biochemistry.
authors.forename: Jolyn E
authors.initials: JE
authors.lastname: Gisselberg
authors.affiliation: ‖Chemical and Systems Biology, Stanford Medical School, Stanford University, Stanford, California 94025.
authors.forename: Lichao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: ‖Chemical and Systems Biology, Stanford Medical School, Stanford University, Stanford, California 94025.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Elias
authors.affiliation: From the ‡Department of Biochemistry, ellenyeh@stanford.edu.|§Pathology.|¶Microbiology and Immunology, and.
authors.forename: Ellen
authors.initials: E
authors.lastname: Yeh
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D013058:Mass Spectrometry / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism* / Q000472:pathogenicity; D011487:Protein Conformation; D017368:Protein Prenylation / Q000187:drug effects*; D040901:Proteomics / Q000379:methods; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D020691:rab GTP-Binding Proteins