Reduced ribosomes of the apicoplast and mitochondrion of Plasmodium spp. and predicted interactions with antibiotics

Abstract

Apicomplexan protists such as Plasmodium and Toxoplasma contain a mitochondrion and a relic plastid (apicoplast) that are sites of protein translation. Although there is emerging interest in the partitioning and function of translation factors that participate in apicoplast and mitochondrial peptide synthesis, the composition of organellar ribosomes remains to be elucidated. We carried out an analysis of the complement of core ribosomal protein subunits that are encoded by either the parasite organellar or nuclear genomes, accompanied by a survey of ribosome assembly factors for the apicoplast and mitochondrion. A cross-species comparison with other apicomplexan, algal and diatom species revealed compositional differences in apicomplexan organelle ribosomes and identified considerable reduction and divergence with ribosomes of bacteria or characterized organelle ribosomes from other organisms. We assembled structural models of sections of Plasmodium falciparum organellar ribosomes and predicted interactions with translation inhibitory antibiotics. Differences in predicted drug-ribosome interactions with some of the modelled structures suggested specificity of inhibition between the apicoplast and mitochondrion. Our results indicate that Plasmodium and Toxoplasma organellar ribosomes have a unique composition, resulting from the loss of several large and small subunit proteins accompanied by significant sequence and size divergences in parasite orthologues of ribosomal proteins.

Keywords: Apicomplexa; antibiotics; large subunit (LSU) proteins; organelles; ribosomes; small subunit (SSU) proteins.

Figure 1.

A five-set Venn diagram showing the distribution of nuclear- or plastid-encoded ribosomal proteins that would constitute the plastid ribosomes of apicomplexans P. falciparum and T. gondii, red alga C. merolae, green alga C. reinhardtii and diatom T. pseudonana.

Figure 2.

Structure models of P. falciparum apicoplast (a) and mitochondrial (b) LSU rRNA and proteins L11, L4 and L22. The rRNA and protein subunits were modelled separately and superimposed on the E. coli ribosome template to generate the ribosome complexes. LSU rRNA is shown in cyan and proteins in red.

Figure 3.

Modelling of antibiotic interactions with P. falciparum organelle ribosomes. (a) Azithromycin docked onto apicoplast (i) and mitochondrial (ii) ribosomes. As in the Thermus thermophilus ribosome–azithromycin structure, a single azithromycin molecule was docked at the binding site. (b) Interaction of clindamycin with apicoplast (i) and mitochondrial (ii) LSU rRNA. Bases that differ between the apicoplast and mitochondrial rRNA are shown in red and H-bonds as black lines. rRNA is in grey, L22 in cyan and antibiotics are in green.

Figure 4.

Predicted interaction of thiostrepton with LSU rRNA and L11 of ribosomes of the P. falciparum apicoplast (a) and mitochondrion (b). rRNA is in grey, L11 in cyan and thiostrepton in green.

Figure 5.

ClustalW alignment of E. coli L11 with L11 predicted for the P. falciparum mitochondrion (a) and apicoplast (b).