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. 2023 Dec 29;14(1):46.
doi: 10.3390/biom14010046.

Plasmodium, the Apicomplexa Outlier When It Comes to Protein Synthesis

José R Jaramillo Ponce  1 , Magali Frugier  1
Affiliations

Plasmodium, the Apicomplexa Outlier When It Comes to Protein Synthesis

José R Jaramillo Ponce et al. Biomolecules. .

Abstract

Plasmodium is an obligate intracellular parasite that has numerous interactions with different hosts during its elaborate life cycle. This is also the case for the other parasites belonging to the same phylum Apicomplexa. In this study, we bioinformatically identified the components of the multi-synthetase complexes (MSCs) of several Apicomplexa parasites and modelled their assembly using AlphaFold2. It appears that none of these MSCs resemble the two MSCs that we have identified and characterized in Plasmodium. Indeed, tRip, the central protein involved in the association of the two Plasmodium MSCs is different from its homologues, suggesting also that the tRip-dependent import of exogenous tRNAs is not conserved in other apicomplexan parasites. Based on this observation, we searched for obvious differences that could explain the singularity of Plasmodium protein synthesis by comparing tRNA genes and amino acid usage in the different genomes. We noted a contradiction between the large number of asparagine residues used in Plasmodium proteomes and the single gene encoding the tRNA that inserts them into proteins. This observation remains true for all the Plasmodia strains studied, even those that do not contain long asparagine homorepeats.

Keywords: AlphaFold2 modeling; amino acid usage; multi-synthetase complexes; tRNA; translational control.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Phylogeny of Apicomplexa parasites. Most members of the Apicomplexa phylum are obligate parasites, some of which cause diseases in vertebrates. Their life cycle consists of three stages: sporozoite (infective stage), merozoite (asexual reproduction), and gametocyte (sexual reproduction). Apicomplexa are characterized by the presence of an apical complex responsible for the invasion of the parasite into the host cells and most of them possess an apicoplast, a plastid essential for their survival (reviewed in [18]). The phylum is divided into two classes: Aconoidasida and Conoidasida. On the one hand, the Conoisada include all species of Cryptosporidium: C. hominis, C. parvum, and C. muris, among others, as well as Neospora and Toxoplasma. On the other hand, the Aconoidasida can be classified into Haemosporida, consisting of Plasmodium species and Piroplasmida that include Theileria and Babesia species. This classification is the one used by the VEupathDB database (https://veupathdb.org (accessed on 22 November 2023)) [19]. Apicopmplexa species considered in this study are indicated in orange (Plasmodia) and blue (others).
Figure 2
Figure 2
Proteins potentially involved in GST-like driven complexes in Apicomplexa parasites. For each Apicomplexa genera, homologous proteins (blue) to Plasmodium GST-like-containing proteins (orange) were identified by BLAST. Their additional domains located at their C-terminus are shown, as well as the presence of a putative interface 2 in the GST-like domains (indicated by α7). GST-like domains are found exclusively in eukaryotes. They are most abundant in mammals where they are found fused to EPRS, MRS, AIMP2, and AIMP3, which are part of the MSC. The GST-like domains of VRS and Ef1-γ interact, and a GST-containing CRS is produced by alternative splicing in humans and also interacts with eEF1-γ (reviewed in [12]). Other domains appended to Apicomplexa aaRSs have been identified and are shown in (Table S1B).
Figure 3
Figure 3
Structure and oligomerization of GST-like domains in eukaryotic MSCs and EF1. (A) Topological diagram and cartoon representation of a GST-like domain. The drop shape represents the orientation of the GST-like domain with oligomerization interfaces 1, 1′, and 2 highlighted. All secondary structures (α-helices and β-strands), and the N- and C-terminal ends are indicated. The thioredoxin-like subdomain (β1-α1-β2-β3-β4-α2) is colored in green, and the C-terminal helical subdomain is shown in purple (helices α3 to α7). Additional α-helices observed in some Apicomplexa GST-like domains are in grey. The position of the N-capping box and hydrophobic staple motif in helix α5 is colored in light blue. The model depicted in cartoon corresponds to the GST-like domain of T. gondii MRS predicted with ColabFold v.1.5.3 in complex with Tg-p43 and ERS. (B) Interaction interfaces involved in homo- and hetero-dimerization of GST-like domains. In each case, the drop shape representation, and the topological diagram of the GST-like dimer are shown. Interacting helices are colored in green and their contact patterns are indicated with red arrows. Interface 1 corresponds to a classical GST dimer, the two monomers being related by a 2-fold axis and interacting mainly through helices α2 and α3 in a parallel orientation. Interface 1′ is only observed in the crystal structure of P. vivax tRip, in which the N-termini of the two monomers are located on the same side of the homodimer and the interacting helices α2 and α3 are oriented perpendicularly. Interface 2 involves helix α7 and the loop connecting helices α4 and α5. A stacking interaction between two arginines from helices α7 is essential for dimerization and these residues are conserved only in GST-like domains from EF1-β, EF1-γ, ERS, and AIMPs.
Figure 4
Figure 4
Predicted interactions between MSC GST-like domains in yeast and Apicomplexa parasites: (A) Pairwise interactions. Homo- and hetero-dimers were predicted with ColabFold using the sequences of the GST-like domains involved in yeast and Apicomplexa MSCs. For each combination of dimers, the occurrence of canonical GST-like interfaces 1, 1′, or 2 is indicated by a gradient of green, yellow, and blue, respectively. The score corresponds to the number of models displaying these interfaces (n = 5). (B) ColabFold predictions of heteromeric GST-like complexes are schematized with drop shape, with AIMP colored in grey, ERS in black, QRS in blue, and MRS in orange, and displaying interfaces 1, 1′, and 2. The S. cerevisiae, T. parva, and B. bovis MSCs contain 3 GST-like domains; AIMP binds MRS via interface 1 and ERS via interface 2. The 4 GST-like domains of P. berghei, T. gondii, and N. caninum share the same interaction network: AIMP and ERS heterodimerize through interface 2, QRS binds interface 1 of ERS, and MRS interface 1 of AIMP. However, it has been demonstrated that these domains form 2 independent complexes in Plasmodium [13,16] and that Tg-p43 is a dimer that belongs to a single MSC in solution [28].
Figure 5
Figure 5
Composition and architecture of Apicomplexa MSC complexes. MSC models of (A) Plasmodia [13], (B) Theileria and Babesia, and (C) Toxoplasma and Neospora are shown. Color code is the same as in the legend of Figure 4. Schematic views of the complexes are built from GST-like domains (drops), minimal core enzymes (catalytic domain and the anticodon-binding domain), and additional RNA-binding domains. An EMAPII-like domain is appended to the C-terminus of MRSs (except in Theileria and Babesia complexes) and a positively charged helix is attached at the C-terminus of QRSs. These domains provide additional non-specific tRNA-binding properties to the aaRSs present in MSCs [13]. The EMAP-II like domain of AIMPs could be involved in the binding of different tRNAs, either host tRNAs in Plasmodium (A) or endogenous tRNAGlu and tRNAMet in Theileria and Babesia (B). In Toxoplasma and Neospora, for clarity, only one half of the MSC is shown. The YRS is a dimer with 2 N-terminal helical domains (black), but no interaction interface can be proposed. All endogenous tRNAs are now shown in grey and host tRNAs are in green.
Figure 6
Figure 6
tRNA gene content in the selected Apicomplexa genomes. The tRNA genes were retrieved directly from annotated genomes of Plasmodia, B. bovis, B. microti, T. orientalis, T. parva, C. hominis, C. muris, T. gondii, and N. caninum (EupathDB). There are indicated in black. The tRNA genes identified using the tRNAscan-SE in B. bigemina, T. annulata, and C. parvum are shown in green. Some “missing” tRNAs in the genomes of B. bigemina, B. microti, C. muris, and N. caninum were found manually by BLAST with a sequence from an organism of the same genus, and are indicated in red. The number of tRNA genes and genome sizes are shown in orange for Plasmodia and in blue for other Apicomplexa.
Figure 7
Figure 7
Comparison of tRNA usage in Apicomplexa parasites: (A) Correlation between proteome size and the number of tRNA genes in Plasmodia (orange) and other Apicoplexa (Blue). Data are from Figure 6. (B) tRNA usage displayed as amino acids decoded per tRNA gene (all isoacceptors together) in Plasmodia (orange) and other Apicomplexa parasites (blue). Some Plasmodia tRNAs (Asp, Ile, Lys, Asn, and Tyr) are potentially highly utilized during translation, compared to their homologues in other Apicomplexa parasites. (C) tRNA usage displayed as amino acid homorepeats decoded per tRNA gene (all isoacceptors together).
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References

    1. Janouskovec J., Paskerova G.G., Miroliubova T.S., Mikhailov K.V., Birley T., Aleoshin V.V., Simdyanov T.G. Apicomplexan-like Parasites Are Polyphyletic and Widely but Selectively Dependent on Cryptic Plastid Organelles. eLife. 2019;8:e49662. doi: 10.7554/eLife.49662. - DOI - PMC - PubMed
    1. Chandley P., Ranjan R., Kumar S., Rohatgi S. Host-Parasite Interactions during Plasmodium Infection: Implications for Immunotherapies. Front. Immunol. 2023;13:1091961. doi: 10.3389/fimmu.2022.1091961. - DOI - PMC - PubMed
    1. Cowman A.F., Healer J., Marapana D., Marsh K. Malaria: Biology and Disease. Cell. 2016;167:610–624. doi: 10.1016/j.cell.2016.07.055. - DOI - PubMed
    1. Attias M., Teixeira D.E., Benchimol M., Vommaro R.C., Crepaldi P.H., De Souza W. The Life-Cycle of Toxoplasma Gondii Reviewed Using Animations. Parasites Vectors. 2020;13:588. doi: 10.1186/s13071-020-04445-z. - DOI - PMC - PubMed
    1. Matta S.K., Rinkenberger N., Dunay I.R., Sibley L.D. Toxoplasma gondii Infection and Its Implications within the Central Nervous System. Nat. Rev. Microbiol. 2021;19:467–480. doi: 10.1038/s41579-021-00518-7. - DOI - PubMed

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