Limits...
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.

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

License
getmorefigures.php?uid=PMC4042851&req=5

RSOB140045F4: 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.

Mentions: Thiostrepton targets the GTPase associated centre of the 50S ribosome subunit and binds within a cleft between helices 43 and 44 of the LSU rRNA and L11. It overlaps with the position of domain V of elongation factor G (EF-G), thus perturbing the binding of the elongation factor to ribosomes [86]. Plasmodium falciparum organelle LSU rRNAs differ at two residues in the helices: the crucial A1067 site and A1095 (E. coli number) are replaced by G1067 and C1095 in the mitochondrion (figure 4). The former has been shown to alter binding of thiostrepton to the ribosome although introduction of an A1067G mutation in the apicoplast rRNA did not completely abolish in vitro interaction with the antibiotic [87]. It is also important to note the low identity and consequent conformational differences in L11 of the apicoplast and mitochondrion that might influence interaction with thiostrepton. The structural models in figure 4 as well as the ClustalW alignment of E. coli and P. falciparum organelle L11 proteins indicate greater similarity between the bacterial and parasite mitochondrial ribosome–thiostrepton interaction site compared with the apicoplast [86] (figures 4 and 5). The identity between the mitochondrial and apicoplast L11 with the E. coli protein is 24.71% and 10.07%, respectively. In addition to targeting the apicoplast, thiostrepton has also been shown to act on the cytosolic proteasome [80] and has detectable effects on mitochondrial translation [81]. Thiostrepton is also able to partially lock P. falciparum mitochondrial EF-G onto surrogate E. coli ribosomes, an effect not observed with apicoplast EF-G [14].Figure 4.


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)

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

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

RSOB140045F4: 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.
Mentions: Thiostrepton targets the GTPase associated centre of the 50S ribosome subunit and binds within a cleft between helices 43 and 44 of the LSU rRNA and L11. It overlaps with the position of domain V of elongation factor G (EF-G), thus perturbing the binding of the elongation factor to ribosomes [86]. Plasmodium falciparum organelle LSU rRNAs differ at two residues in the helices: the crucial A1067 site and A1095 (E. coli number) are replaced by G1067 and C1095 in the mitochondrion (figure 4). The former has been shown to alter binding of thiostrepton to the ribosome although introduction of an A1067G mutation in the apicoplast rRNA did not completely abolish in vitro interaction with the antibiotic [87]. It is also important to note the low identity and consequent conformational differences in L11 of the apicoplast and mitochondrion that might influence interaction with thiostrepton. The structural models in figure 4 as well as the ClustalW alignment of E. coli and P. falciparum organelle L11 proteins indicate greater similarity between the bacterial and parasite mitochondrial ribosome–thiostrepton interaction site compared with the apicoplast [86] (figures 4 and 5). The identity between the mitochondrial and apicoplast L11 with the E. coli protein is 24.71% and 10.07%, respectively. In addition to targeting the apicoplast, thiostrepton has also been shown to act on the cytosolic proteasome [80] and has detectable effects on mitochondrial translation [81]. Thiostrepton is also able to partially lock P. falciparum mitochondrial EF-G onto surrogate E. coli ribosomes, an effect not observed with apicoplast EF-G [14].Figure 4.

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