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

Gupta A, Shah P, Haider A, Gupta K, Siddiqi MI, Ralph SA, Habib S - Open Biol (2014)

Bottom Line: 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.Differences in predicted drug-ribosome interactions with some of the modelled structures suggested specificity of inhibition between the apicoplast and mitochondrion.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India.

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.

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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.
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RSOB140045F2: 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.

Mentions: Prediction of the three-dimensional structures of parasite organelle ribosomes is demanding due to the difficulty in obtaining high-resolution experimental models. This is further complicated by the presence of highly fragmented rRNA encoded by the P. falciparum mitochondrial genome [11]. A stand-alone version of the RNA prediction tool ModeRNA was used for the comparative modelling of rRNA, whereas modelling of ribosomal proteins L4, L11 and L22 was performed by Modeller v. 9.10. For modelling of the mitochondrial ribosome, different fragments of mitochondrial LSU rRNA were aligned manually on the basis of conserved secondary structure topology, modelled separately and then superimposed together on the E. coli template to obtain a complex RNA model structure. All the modelled subunits (rRNA and protein) were superimposed on the E. coli ribosome template to generate the apicoplast and mitochondrial ribosome complexes (figure 2). The fragmented rRNA comprising the core of the mitochondrial ribosome is highly reduced, though retains conservation of the peptidyl transferase centre and the peptide exit tunnel where most antibiotics bind.FigureĀ 2.


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

Gupta A, Shah P, Haider A, Gupta K, Siddiqi MI, Ralph SA, Habib S - Open Biol (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042851&req=5

RSOB140045F2: 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.
Mentions: Prediction of the three-dimensional structures of parasite organelle ribosomes is demanding due to the difficulty in obtaining high-resolution experimental models. This is further complicated by the presence of highly fragmented rRNA encoded by the P. falciparum mitochondrial genome [11]. A stand-alone version of the RNA prediction tool ModeRNA was used for the comparative modelling of rRNA, whereas modelling of ribosomal proteins L4, L11 and L22 was performed by Modeller v. 9.10. For modelling of the mitochondrial ribosome, different fragments of mitochondrial LSU rRNA were aligned manually on the basis of conserved secondary structure topology, modelled separately and then superimposed together on the E. coli template to obtain a complex RNA model structure. All the modelled subunits (rRNA and protein) were superimposed on the E. coli ribosome template to generate the apicoplast and mitochondrial ribosome complexes (figure 2). The fragmented rRNA comprising the core of the mitochondrial ribosome is highly reduced, though retains conservation of the peptidyl transferase centre and the peptide exit tunnel where most antibiotics bind.FigureĀ 2.

Bottom Line: 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.Differences in predicted drug-ribosome interactions with some of the modelled structures suggested specificity of inhibition between the apicoplast and mitochondrion.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India.

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.

Show MeSH