A genomic glimpse of aminoacyl-tRNA synthetases in malaria parasite Plasmodium falciparum
© Bhatt et al; licensee BioMed Central Ltd. 2009
Received: 3 July 2009
Accepted: 31 December 2009
Published: 31 December 2009
Plasmodium parasites are causative agents of malaria which affects >500 million people and claims ~2 million lives annually. The completion of Plasmodium genome sequencing and availability of PlasmoDB database has provided a platform for systematic study of parasite genome. Aminoacyl-tRNA synthetases (aaRS s) are pivotal enzymes for protein translation and other vital cellular processes. We report an extensive analysis of the Plasmodium falciparum genome to identify and classify aaRSs in this organism.
Using various computational and bioinformatics tools, we have identified 37 aaRS s in P. falciparum. Our key observations are: (i) fraction of proteome dedicated to aaRS s in P. falciparum is very high compared to many other organisms; (ii) 23 out of 37 Pf-aaRS sequences contain signal peptides possibly directing them to different cellular organelles; (iii) expression profiles of Pf-aaRSs vary considerably at various life cycle stages of the parasite; (iv) several PfaaRSs posses very unusual domain architectures; (v) phylogenetic analyses reveal evolutionary relatedness of several parasite aaRS s to bacterial and plants aaRSs; (vi) three dimensional structural modelling has provided insights which could be exploited in inhibitor discovery against parasite aaRSs.
We have identified 37 Pf-aaRSs based on our bioinformatics analysis. Our data reveal several unique attributes in this protein family. We have annotated all 37 Pf-aaRSs based on predicted localization, phylogenetics, domain architectures and their overall protein expression profiles. The sets of distinct features elaborated in this work will provide a platform for experimental dissection of this family of enzymes, possibly for the discovery of novel drugs against malaria.
Aminoacylation is the process of adding an aminoacyl group to the 3' end (CCA) of the tRNA molecule. tRNA is aminoacylated with a specific amino acid by aminoacyl-tRNA synthetase (aaRS s). aaRS s are responsible for attaching correct amino acid onto the cognate tRNA molecule in a two-step reaction. The amino acid is first activated with ATP forming an aminoacyladenylate intermediate. Once activated, this amino acid is transferred to the 3' end of its corresponding tRNA molecule to be processed during protein synthesis. All aaRSs require divalent cation MgCl2 for their aminoacylation reaction [1, 2].
amino acid + ATP → aminoacyl-AMP + PPi
aminoacyl-AMP + tRNA → aminoacyl-tRNA + AMP
The aaRS s are divided into two major classes based on structural topology of their active sites. Class I aaRS s represent 11 amino acids, including Arg, Cys, Gln, Glu, Ile, Leu, Lys, Met, Val, Trp and Tyr. Class II aaRS s includes 10 amino acids - Ala, Asp, Asn, Gly, His, Lys, Phe, Pro, Ser and Thr. Core domains of class I enzymes are characterized by a Rossmann fold which consists of α-helices and β-pleated sheets. This domain contains two conserved motifs ('HIGH' and 'KMSKS') which are directly involved in ATP binding. Catalytic domain of class II enzymes has a unique fold with a central core of anti-parallel β strands flanked by α helices . There are three weakly conserved motifs, two of them are involved in ATP binding while the third one plays a role in homo dimerization. Class I enzymes bind ATP in an extended conformation while class II do so in a bent conformation. The two aaRS classes have different modes of aminoacylation - class I enzymes aminoacylate the 2'OH of the cognate tRNA whereas class II enzymes aminoacylate 3'OH of the tRNA (with the exception of PheRS) . All known aaRS s are multidomain proteins with complex modular architectures . In addition, eukaryotic aaRSs are distinguished by the presence of appended domains at either the N- or C-terminus which are generally absent from their bacterial/archaeal counterparts . These appendages to the catalytic cores of several aaRSs are non-catalytic and instead function to mediate protein- protein interactions or act as general RNA-binding domains [7–9].
In mammalian cells, some aaRS s are present as a larger multi- aaRS complex (MSC) composed of nine synthetases (arginyl-, aspartyl-, glutamyl-, glutaminyl-, leucyl-, lysyl-, isoleucyl-, methionyl- and prolyl-tRNA synthetases) [10–12]. The MSC is composed of a mixture of class I and class II aaRS s along with three non- aaRS proteins p38, p43 and p18. It is not clear why certain aaRS s exist as a complex while some are in free form. MSC might help in efficient protein synthesis by preventing mixing of charged tRNAs with cellular pool and by increasing local concentration of tRNA near the site of protein synthesis .
The accuracy of tRNA aminoacylation reaction is critical in ensuring fidelity in protein translation . To achieve this accuracy, some aaRS enzymes possess a proofreading (editing) mechanism that hydrolyzes tRNAs aminoacylated with the non-cognate amino acid . For example, editing domains may be found attached to alanyl-tRNA synthetase (AlaRS), leucyltRNA synthetase (LeuRS) and so on [16–21]. In other cases, the editing domain is not attached to aaRS but rather functions as an individual protein [22, 23]. For example, YbaK protein from Haemophilus influenza is capable of efficiently editing Cys-tRNAPro. ThrRS has been shown to have another editing domain called NTD which can cleave the bond between D-amino acid and tRNA .
Recently it has been shown that aaRS s are not only involved in protein synthesis but also perform many non-catalytic and non-canonical roles in RNA processing/trafficking, apoptosis, rRNA synthesis, angiogenesis and inflammation [26–30]. These versatile properties of aaRS s are the outcome of their differential cellular localization, nucleic acid binding properties, protein-protein interactions and collaboration (fusion) with additional domains. In case of malaria parasite, apicoplast proteins and pathways have already received particular attention as drug targets . In this work we present a study of aaRS s from P. falciparum - the most virulent agent of human malaria. Our aim for this study was to use bioinformatics tools to (a) discover special and unusual modules present in parasite aaRSs which are potentially absent from human homologues, and (b) to identify potential new drug targets based on this protein family.
Results and Discussion
Sequence extraction and analysis
Results of database searches by HMM models of aaRS@.
c > 50
20< c < 50
10< c < 20
5< c <10
c > 50
20< c < 50
10< c < 20
5< c <10
Indirect pathways of aminoacylation
It was earlier believed that 20 aaRS s were necessary for the incorporation of 20 amino acids in proteins. But surprisingly, some archaea, bacteria and chloroplasts lack GlnRS and AsnRS enzymes [34–38]. Interestingly, these organisms use an alternate pathway based on tRNA dependent amino acid transformation. A non-discriminating GluRS charges tRNAGln with glutamic amino acid and then a second enzyme called tRNA-dependent amidotransferase (AdT) amidates glutamate to make glutamine. A corresponding reaction occurs in case of asparagine residues. In case of P. falciparum, occurrence of glutamate-tRNA synthetase (PF13_0257, MAL13P1.281) and amidotransferase subunit A (PFD0780w) & subunit B (PFF1395c) together indicates presence of both direct and indirect pathways for aminoacylation [39, 40]. Both subunits of amidotransferase have apicoplast targeting signals suggesting an indirect pathway for aminoacylation in P. falciparum apicoplast. The expression of Pf-AdT subunit A is predicted in all life cycle stages of parasite based on proteomic and microarray data. We therefore feel that this pathway must also be active in the parasite apicoplast. We could not find sequence homologues of enzymes involved in indirect aminoacylation of cysteine residues [41–43] in the proteome of P. falciparum.
The multi-synthetase complex (MSC)
In mammalian cells, some aaRS s are present as a larger multi-aaRS complex (MSC). A constituent of the MSC - protein p43 - has sequence homologue (PF14_0401 - EMAP-II-like cytokine) in P. falciparum although there is no evidence for presence of MSC in malaria parasites. Interestingly, p43 is not only required for stability of the MSC complex but also functions as a proinflammatory cytokine [44–46]. Role of p43 homolog in P. falciparum is unknown, but evidence from other organisms indicates that MSC functions in protein stability, efficient protein translation and protein elongation . Sequence identity between P. falciparum p43 and its human homolog is ~24% and based on microarray data p43 seems to be expressed at asexual life cycle stages of P. falciparum. A mitochondrial targeting signal was also predicted for parasite p43 but the role of p43 in parasite remains to be explored experimentally.
Targeting of aaRSs in the parasite
Expression profiles of P. falciparum aaRSs
Transcriptomic and proteomic data for aaRSs in P. falciparum@
Domain architecture of P. falciparum aaRSs
Homology modeling and structure comparisons
Structural differences between tyrosyl-tRNA synthetases from human & P. falciparum
Hs-TyrRS (1N3L) !
Pf-TyrRS (MAL8P1.125) $
Residues involved in tyrosine and A73 recognition
Aminoacyl-tRNA synthetases (aaRS s) link RNA with protein translation. Besides their key role in protein synthesis, aaRS s are also integral to various other cellular processes. aaRS enzymes have been the focus for antimicrobial drug discovery [64, 65]. An example of clinical application of an aaRS inhibitor is provided by the antibiotic mupirocin (marketed as Bactroban), which selectively inactivates bacterial isoleucyl-tRNA synthetase . Similarly, it has been shown that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690) inhibits yeast cytoplasmic leucyl-tRNA synthetase by blocking editing site of the enzyme [67, 68]. Therefore, presence of distinct or tinkered P. falciparum aaRS lends an opportunity for their exploitation as new drug targets against malaria. In this study, we have extensively analyzed aaRS sequences from Plasmodium species in terms of their mRNA/protein expression profiles, their cellular localization, their organelle targeting and their unique sequence/domain attributes. We have discovered several distinct aaRS s in P. falciparum with no clear human counterparts in terms of their overall domain structures. We have also highlighted deviations of some highly conserved sequence motifs and active site sequence clusters. Our analyses clearly show that a larger fraction of P. falciparum proteome is devoted to aaRS when compared with many other organisms. The phylogenetic data hint at evolutionary closeness of some Pf-aaRSs to bacteria and plants - this further supports the fact of secondary endosymbiosis in this apicomplexan. We hope that our in-depth phylogenetic, protein targeting, domain architecture, protein expression profiling and homology modeling data on Pf-aaRSs can be used as a platform for experimental studies of this important protein family in malaria parasites.
The P. falciparum genome database PlasmoDB Release 5.4 was used for the present analyses. Sequence sets of all the aaRS s from other organisms includes P. berghei, P. chabaudi, P. falciparum, P. knowlesi, P. yoelii, P. vivax, H. sapiens, M. tuberculosis, D. discoidium, M. jannaschii, R. norvegicus, C. parvum, B. bovis, S. cerevisiae, D. melanogaster, Y. pestis, T. aquaticus, S. pneumoniae, S. entrica, E. coli, A. thaliana, A. pisum, A. salmonicida, B. cereus, B. thuringiensis, B. afzelii, B. burgdorferi, B. garinii, B. valaisiana, Bradyrhizobium, B. pennsylvanicus, C. acidaminovorans, H. defensa, C. taiwanensis, E. fergusonii, F. bacterium, F. novicida, F. tularensis, F. alni, G. tenuistipitata, H. arsenicoxydans, A. cellulolyticus, A. chlorophenolicus, A. ferrooxidans, Algoriphagus, A. muciniphila, Anaeromyxobacter, A. thermophilum, B. ambifaria, B. indica, B. mycoides, B. taurus, B. tribocorum, C. atlanticus, Caulobacter, C. aurantiacus, C. cellulolyticum, Citrobacter, C. pinensis, C. Ruthia, Cyanothece, D. desulfuricans, D. hafniense, Diaphorobacter, D. shibae, D. turgidum, E. cuniculi, E. lenta, E. ruminantium, Exiguobacterium, G. diazotrophicus, Geobacillus, M. maris, N. multipartita, Nocardioides, O. terrae, P. abelii, P. atlantica, P. denitrificans, P. ingrahamii, P. lavamentivorans, R. castenholzii, S. arenicola, S. fumaroxidans, X. autotrophicus, V. vadensis, V. paradoxus, T. whipplei, T. auensis, S. stellata, Ch. parvum, S. heliotrinireducens, Silicibacter, S. putrefaciens, S. usitatus, Thauera, X. laevis, Theileria annulata, Vibrio fischeri, W. succinogenes, X. tropicalis, Zeamays. Additional sequences were obtained based on sequence similarity via NCBI BLAST  and ENSEMBL  databases. Known sequence motifs of aaRS s have been used as templates to retrieve sequences of aaRS from other organisms. Some aaRS sequences were manually annotated based on the presence of signature motifs. Protein domains and motifs in the predicted aaRS s were identified using following programs - Superfamily , SMART  and MotifScan available at expasy web server. The following databases - Pfam , TIGR, PIR, EBI and PlasmoDB were also extensively used. Hidden Markov Model (HMM) for each of the 20 aaRS were constructed by the software package Sequence Alignment and Modeling System version 2.2.1 (SAM)  exploiting sequences in the aaRS database . HMM profiles were then used to carry out database search vs P. falciparum proteins. A score was assigned to each protein by calculating the probability that the corresponding sequence is generated by the HMM model, hence for each database search a score distribution was obtained. The score distributions were normalized and 4 ranges of values were considered to identify aaRS (c > 5, 10 < c < 20, 20 < c < 50, c < 50).
Expression and Localization
The prediction of signal sequences for cellular localization in P. falciparum was performed using various available online web-servers - MITOPROT , PredictNLS  and PATS  for mitochondria, nucleus and apicoplast respectively. PEXEL motif prediction was been carried out by querying PlasmoDB. To identify specific gene expression profiles, we have combined information from different data sets. For the spotted oligonucleotide array data, only half of the 48 time points of the intra-erythrocytic cycle are shown for simplicity, and ratios (versus a common reference) were log2-transformed prior to cluster analysis. For the photolithography data, CEL files were downloaded from website and transferred into Bioconductor package for analysis using a robust multi-array averaging algorithm (RMA) for background adjustment and quantiles normalization . Genes whose expression level was less than 10 (too close to background) or the logP was greater than -0.5 (too few probes per gene) were removed from dataset. Total intensity values for each time point were converted to mean-centered ratios by dividing the total intensity by the average intensity for that gene across all experimental conditions and were then log2-transformed prior to clustering. These data manipulations were necessary because the oligo-nucleotide array data was collected as the intensity ratio between the experimental sample and a common reference, while the photolithography data was collected as the total signal intensity at each spot. Gene expression patterns where the minimum percentage of existing values was less than 80% were eliminated from rest of the analysis. The remaining missing values were replaced by using the KNN-imputation method .
To explore the evolutionary relationships amongst aaRSs phylogenetic analyses were performed for each P. falciparum aaRS on an expanded set of 102 sequences. Multiple sequence alignments of these sequences were obtained from CLUSTALW with default parameters (performed locally) in PHYLIP format . These MSAs were used as seed sequences to run PHYML_v2.4.4 using Jones-Taylor-Thornton (JTT) model . The resulting file was further used in MEGA4.2 for visualization of trees .
Model Building and Validation
We used Sali's Modeller8v2  tool for building various P. falciparum aaRS s models. The stereo-chemical quality of modeled proteins was verified by PROCHECK . Structural mapping of active site residues and other motifs was performed using CHIMERA  and PYMOL .
TKB, CK and AS are supported by grants from the Department of Biotechnology, Govt. Of India. SK is supported by MEPHITIS grant. This work has been conducted as part of MEPHITIS project and partially funded by the European Commission (Grant Agreement no: HEALTH-F3-2009-223024).
- Ibba M, Soll D: Aminoacyl-tRNA synthesis. Annu Rev Biochem. 2000, 69: 617-650. 10.1146/annurev.biochem.69.1.617.View ArticlePubMedGoogle Scholar
- Ibba M, Soll D: The renaissance of aminoacyl-tRNA synthesis. EMBO Rep. 2001, 2: 382-387.PubMed CentralView ArticlePubMedGoogle Scholar
- Eriani G, Delarue M, Poch O, Gangloff J, Moras D: Partition of tRNA synthetases into two classes based on mutually exclusive sets of sequence motifs. Nature. 1990, 347: 203-206. 10.1038/347203a0.View ArticlePubMedGoogle Scholar
- Burbaum JJ, Schimmel P: Structural relationships and the classification of aminoacyl- tRNA synthetases. J Biol Chem. 1991, 266: 16965-16968.PubMedGoogle Scholar
- Wolf YI, Aravind L, Grishin NV, Koonin EV: Evolution of aminoacyl-tRNA synthetases-analysis of unique domain architectures and phylogenetic trees reveals a complex history of horizontal gene transfer events. Genome Res. 1999, 9 (8): 689-710.PubMedGoogle Scholar
- Mirande M: Aminoacyl tRNA synthetase family from prokaryotes and eukaryotes: structural domains and their implications. Prog Nucleic Acid Res Mol Biol. 1991, 40: 95-142. full_text.View ArticlePubMedGoogle Scholar
- Cahuzac B, Berthonneau E, Birlirakis N, Guittet E, Mirande M: A recurrent RNA binding domain is appended to eukaryotic aminoacyl-tRNA synthetases. EMBO J. 2000, 19: 445-452. 10.1093/emboj/19.3.445.PubMed CentralView ArticlePubMedGoogle Scholar
- Robinson JC, Kerjan P, Mirande M: Macromolecular assemblage of aminoacyl-tRNA synthetases: quantitative analysis of protein-protein interactions and mechanism of complex assembly. J Mol Biol. 2000, 304: 983-994. 10.1006/jmbi.2000.4242.View ArticlePubMedGoogle Scholar
- Guigou L, Shalak V, Mirande M: The tRNA-interacting factor p43 associates with mammalian arginyl-tRNA synthetase but does not modify its tRNA aminoacylation properties. Biochemistry. 2004, 43: 4592-4600. 10.1021/bi036150e.View ArticlePubMedGoogle Scholar
- Hausmann CD, Ibba M: Aminoacyl-tRNA synthetase complexes: molecular multitasking revealed. FEMS Microbiology Reviews. 2008, 32: 705-721. 10.1111/j.1574-6976.2008.00119.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Bandyopadhyay AK, Deutscher MP: Complex of aminoacyl-transfer RNA synthetases. J Mol Biol. 1971, 60: 113-122. 10.1016/0022-2836(71)90451-7.View ArticlePubMedGoogle Scholar
- Kerjan P, Cerini C, Semeriva M, Mirande M: The multienzyme complex containing nine aminoacyl-tRNA synthetases is ubiquitous from Drosophila to mammals. Biochem Biophys Acta. 1994, 1199: 293-297.View ArticlePubMedGoogle Scholar
- Wolfson A, Knight R: Occurrence of the aminoacyl-tRNA synthetases in high-molecular weight complexes correlates with the size of substrate amino acids. FEBS Lett. 2005, 579: 3467-3472. 10.1016/j.febslet.2005.05.038.View ArticlePubMedGoogle Scholar
- Schimmel P, Schmidt E: Residues in a class I tRNA synthetase which determine selectivity of amino acid recognition in the context of tRNA. Biochemistry. 1995, 34: 11204-11210. 10.1021/bi00035a028.View ArticlePubMedGoogle Scholar
- Lin L, Schimmel P: Mutational analysis suggests the same design for editing activities of two tRNA synthetases. Biochemistry. 1996, 35: 5596-5601. 10.1021/bi960011y.View ArticlePubMedGoogle Scholar
- Sokabe M, Okada A, Yao M, Nakashima T, Tanaka I: Molecular basis of alanine discrimination in editing site. Proc Natl Acad Sci USA. 2005, 102: 11669-11674. 10.1073/pnas.0502119102.PubMed CentralView ArticlePubMedGoogle Scholar
- Sokabe M, Ose T, Nakamura A, Tokunaga K, Nureki O, Yao M, Tanaka I: The structure of alanyl-tRNA synthetase with editing domain. Proc Natl Acad Sci U S A. 2009, 106 (27): 11028-11033.PubMed CentralView ArticlePubMedGoogle Scholar
- Tardif KD, Liu M, Vitseva O, Hou YM, Horowitz J: Misacylation and editing by Escherichia coli valyl-tRNA synthetase: evidence for two tRNA binding sites. Biochemistry. 2001, 40: 8118-8125. 10.1021/bi0103213.View ArticlePubMedGoogle Scholar
- Betha AK, Williams AM, Martinis SA: Isolated CP1 domain of Escherichia coli leucyl- tRNA synthetase is dependent on flanking hinge motifs for amino acid editing activity. Biochemistry. 2007, 46: 6258-6267. 10.1021/bi061965j.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhao MW, Zhu B, Hao R, Xu MG, Eriani G, Wang ED: Leucyl-tRNA synthetase from the ancestral bacterium Aquifex aeolicus contains relics of synthetase evolution. Embo J. 2005, 24: 1430-1439. 10.1038/sj.emboj.7600618.PubMed CentralView ArticlePubMedGoogle Scholar
- Ambrogelly A, Ahel I, Polycarpo C: Methanocaldococcus jannaschii prolyl-tRNA synthetase charges tRNAPro with cysteine. J Biol Chem. 2002, 277: 34749-34754. 10.1074/jbc.M206929200.View ArticlePubMedGoogle Scholar
- Ruan B, Söll D: The bacterial YbaK protein is a Cys-tRNAPro and Cys-tRNACys deacylase. J Biol Chem. 2005, 280: 25887-25891. 10.1074/jbc.M502174200.View ArticlePubMedGoogle Scholar
- Chong YE, Yang XL, Schimmel P: Natural homolog of tRNA synthetase editing domain rescues conditional lethality caused by mistranslation. J Biol Chem. 2008, 283: 30073-30078. 10.1074/jbc.M805943200.PubMed CentralView ArticlePubMedGoogle Scholar
- An S, Musier-Forsyth K: Trans-editing of Cys-tRNAPro by Haemophilus influenzae YbaK protein. J Biol Chem. 2004, 279: 42359-42362. 10.1074/jbc.C400304200.View ArticlePubMedGoogle Scholar
- Dwivedi S, Kruparani SP, Sankaranarayanan R: A D-amino acid editing module coupled to the translational apparatus in archaea. Nat Struct Mol Biol. 2005, 12: 556-7. 10.1038/nsmb943.View ArticlePubMedGoogle Scholar
- Ko YG, Kang YS, Kim EK, Park SG, Kim S: Nucleolar localization of human methionyl-tRNA synthetase and its role in ribosomal RNA synthesis. J Cell Biol. 2000, 149: 567-574. 10.1083/jcb.149.3.567.PubMed CentralView ArticlePubMedGoogle Scholar
- Martinis SA, Plateau P, Cavarelli J, Florentz C: Aminoacyl-tRNA synthetases: a family of expanding functions. EMBO J. 1999, 18: 4591-4596. 10.1093/emboj/18.17.4591.PubMed CentralView ArticlePubMedGoogle Scholar
- Cherniack AD, Garriga G, Kittle JD, Akins RA, Lambowitz AM: Function of Neurospora mitochondrial tyrosyl-tRNA synthetase in RNA splicing requires an idiosyncratic domain not found in other synthetases. Cell. 1990, 62: 745-755. 10.1016/0092-8674(90)90119-Y.View ArticlePubMedGoogle Scholar
- Sampath P, Mazumder B, Seshadri V, Gerber CA, Chavatte L, Kinter M, Ting SM, Dignam JD, Kim S, Driscoll DM, Fox PL: Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation. Cell. 2004, 119: 147-148. 10.1016/j.cell.2004.09.030.View ArticleGoogle Scholar
- Herzog W, Muller K, Huisken J, Stainier DYR: Genetic evidence for a noncanonical function of seryl-tRNA synthetase in vascular development. Circulation Research. 2009, 104: 1260-1266. 10.1161/CIRCRESAHA.108.191718.PubMed CentralView ArticlePubMedGoogle Scholar
- Ramya TNC, Karmodiya K, Surolia A, Surolia N: 15-Deoxyspergualin Primarily Targets the Trafficking of Apicoplast Proteins in Plasmodium falciparum. J Biol Chem. 2007, 282: 6388-6397. 10.1074/jbc.M610251200.View ArticlePubMedGoogle Scholar
- Stoeckert CJ, Fischer S, Kissinger JC, Heiges M, Aurrecoechea C, Gajria B, Roos DS: PlasmoDB v5: new looks, new genomes. Trends Parasitol. 2006, 22: 543-546. 10.1016/j.pt.2006.09.005.View ArticlePubMedGoogle Scholar
- Francklyn C, Perona JJ, Puetz J, Hou YM: Aminoacyl-tRNA synthetases: Versatile players in the changing theater of translation. RNA. 2002, 8: 1363-1372. 10.1017/S1355838202021180.PubMed CentralView ArticlePubMedGoogle Scholar
- Feng L, Sheppard K, Tumbula-Hansen D, Söll D: Gln-tRNAGln formation from Glu-tRNAGln requires cooperation of an asparaginase and a Glu-tRNAGln kinase. J Biol Chem. 2005, 280: 8150-8155. 10.1074/jbc.M411098200.View ArticlePubMedGoogle Scholar
- Tumbula DL, Becker HD, Chang WZ, Söll D: Domain-specific recruitment of amide amino acids for protein synthesis. Nature. 2000, 407: 106-110. 10.1038/35024120.View ArticlePubMedGoogle Scholar
- Sheppard K, Akochy PM, Salazar JC, Söll D: The Helicobacter pylori amidotransferase GatCAB is equally efficient in glutamine-dependent transamidation of Asp-tRNAAsn and Glu-tRNAGln. J Biol Chem. 2007, 282: 11866-11873. 10.1074/jbc.M700398200.View ArticlePubMedGoogle Scholar
- Schön A, Kannangara CG, Gough S, Söll D: Protein biosynthesis in organelles requires misaminoacylation of tRNA. Nature. 1988, 331: 187-190. 10.1038/331187a0.View ArticlePubMedGoogle Scholar
- Jahn D, Kim YC, Ishino Y, Chen MW, Söll D: Purification and functional characterization of the Glu-tRNA(Gln) amidotransferase from Chlamydomonas reinhardtii. J Biol Chem. 1990, 265: 8059-8064.PubMedGoogle Scholar
- Kim SI, Stange-Thomann N, Martins O, Hong KW, Söll D, Fox TD: A nuclear genetic lesion affecting Saccharomyces cerevisiae mitochondrial translation is complemented by a homologous Bacillus gene. J Bact. 1997, 179: 5625-5627.PubMed CentralPubMedGoogle Scholar
- Sheppard K, Söll D: On the evolution of the tRNA-dependent amidotransferases, GatCAB and GatDE. J Mol Biol. 2008, 377: 831-844. 10.1016/j.jmb.2008.01.016.PubMed CentralView ArticlePubMedGoogle Scholar
- Hauenstein SI, Perona JJ: Redundant synthesis of cysteinyl-tRNACys in Methanosarcina mazei. J Biol Chem. 2008, 283: 22007-22017. 10.1074/jbc.M801839200.PubMed CentralView ArticlePubMedGoogle Scholar
- Sauerwald A, Zhu W, Major TA, Roy H, Palioura S, Jahn D, Whitman WB, Yates JR, Ibba M, Söll D: RNA-dependent cysteine biosynthesis in archaea. Science. 2005, 307: 1969-1972. 10.1126/science.1108329.View ArticlePubMedGoogle Scholar
- Fukunaga R, Yokoyama S: Structural insights into the second step of RNA-dependent cysteine biosynthesis in Archaea: crystal structure of Sep-tRNA:Cys-tRNA synthase from Archaeoglobus fulgidus. J Mol Biol. 2007, 370: 128-141. 10.1016/j.jmb.2007.04.050.View ArticlePubMedGoogle Scholar
- Quevillon S, Agou F, Robinson JC, Mirande M: The p43 component of the mammalian multi-synthetase complex is likely to be the precursor of the endothelial monocyte-activating polypeptide II cytokine. J Biol Chem. 1997, 272: 32573-32579. 10.1074/jbc.272.51.32573.View ArticlePubMedGoogle Scholar
- Behrensdorf HA, van de Craen M, Knies UE, Vandenabeele P, Clauss M: The endothelial monocyte-activating polypeptide II (EMAP II) is a substrate for caspase-7. FEBS Lett. 2000, 466: 143-147. 10.1016/S0014-5793(99)01777-9.View ArticlePubMedGoogle Scholar
- Faisal W, Symonds P, Panjwani S, Heng Y, Murray JC: Cell-surface associated p43/endothelial-monocyte-activating-polypeptide-II in hepatocellular carcinoma cells induces apoptosis in T-lymphocytes. Asian J Surg. 2007, 30: 13-22.View ArticlePubMedGoogle Scholar
- Shalak V, Kaminska M, Mitnacht-Kraus R, Vandenabeele P, Clauss M, Mirande M: The EMAPII cytokine is released from the mammalian multisynthetase complex after cleavage of its p43/proEMAPII component. J Biol Chem. 2001, 276: 23769-23776. 10.1074/jbc.M100489200.View ArticlePubMedGoogle Scholar
- Hopkins J, Fowler R, Krishna S, Wilson I, Mitchell G, Bannister L: The plastid in Plasmodium falciparum asexual blood stages: a three-dimensional ultrastructural analysis. Protist. 1999, 150: 283-295. 10.1016/S1434-4610(99)70030-1.View ArticlePubMedGoogle Scholar
- Lund E, Dahlberg JE: Proofreading and aminoacylation of tRNAs before export from the nucleus. Science. 1998, 282: 2082-2085. 10.1126/science.282.5396.2082.View ArticlePubMedGoogle Scholar
- Cooke BM, Lingelbach K, Bannister LH, Tilley L: Protein trafficking in Plasmodium falciparum -infected red blood cells. Trends Parasitol. 2004, 20: 581-589. 10.1016/j.pt.2004.09.008.View ArticlePubMedGoogle Scholar
- Hiller NL, Bhattacharjee S, van Ooij C, Liolios K, Harrison T: A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science. 2004, 306: 1934-1937. 10.1126/science.1102737.View ArticlePubMedGoogle Scholar
- Le Roch KG, Zhou Y, Blair PL, Grainger M, Moch JK, Haynes JD, De La, Vega P, Holder AA, Batalov S, Carucci DJ, Winzeler EA: Discovery of gene function by expression profiling of the malaria parasite life cycle. Science. 2003, 301: 1487-1488.View ArticleGoogle Scholar
- Bozdech Z, Llinas M, Pulliam BL, Wong ED, Zhu J, DeRisi JL: The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol. 2003, 1: e5-10.1371/journal.pbio.0000005.PubMed CentralView ArticlePubMedGoogle Scholar
- O'Donoghue P, Luthey-Schulten Z: Evolution of Structure in Aminoacyl-tRNA synthetases. Microbiology and Molecular Biology Reviews. 2003, 67: 550-573. 10.1128/MMBR.67.4.550-573.2003.PubMed CentralView ArticlePubMedGoogle Scholar
- Salazar JC, Ambrogelly A, Crain PF, McCloskey JA, Söll D: A truncated aminoacyl-tRNA synthetase modifies RNA. Proc Natl Acad Sci USA. 2004, 101: 7536-7541. 10.1073/pnas.0401982101.PubMed CentralView ArticlePubMedGoogle Scholar
- An S, Musier-Forsyth K: Cys-tRNA(Pro) editing by Haemophilus influenzae YbaK via a novel synthetase.YbaK.tRNA ternary complex. J Biol Chem. 2005, 280: 34465-72. 10.1074/jbc.M507550200.View ArticlePubMedGoogle Scholar
- Dou X, Limmer S, Kreutzer R: DNA-binding of phenylalanyl-tRNA synthetase is accompanied by loop formation of the double-stranded DNA. Journal of Molecular Biology. 2001, 305: 451-458. 10.1006/jmbi.2000.4312.View ArticlePubMedGoogle Scholar
- Seror SJ, Casaregola S, Vannier F, Zoauri N, Dahl M, Boye E: A mutant cysteinyl-tRNA synthetase affecting timing of chromosomal replication initiation in B. subtilis and conferring resistance to a protein kinase C inhibitor. EMBO J. 1994, 13: 2472-2480.PubMed CentralPubMedGoogle Scholar
- Kim JY, Kang YS, Lee JW, Kim HJ, Ahn YH, Park H, Ko YG, Kim S: p38 is essential for the assembly and stability of macromolecular tRNA synthetase complex: implications for its physiological significance. Proc Natl Acad Sci USA. 2002, 99: 7912-7916. 10.1073/pnas.122110199.PubMed CentralView ArticlePubMedGoogle Scholar
- Bec G, Kerjan P, Zha XD, Waller JP: Valyl-tRNA synthetase from rabbit liver. I. Purification as a heterotypic complex in association with elongation factor 1. J Biol Chem. 1989, 264: 21131-21137.PubMedGoogle Scholar
- Bec G, Kerjan P, Waller JP: Reconstitution in vitro of the valyl-tRNA synthetase-elongation factor (EF) 1 beta gamma delta complex. Essential roles of the NH2- terminal extension of valyl-tRNA synthetase and of the EF-1 delta subunit in complex formation. J Biol Chem. 1994, 269: 2086-2092.PubMedGoogle Scholar
- Brandsma M, Kerjan P, Dijik J, Janssen GM, Moller W: Valyl-tRNA synthetase from Artemia. Purification and association with elongation factor 1. Eur J Biochem. 1995, 233: 277-282. 10.1111/j.1432-1033.1995.277_1.x.View ArticlePubMedGoogle Scholar
- Kumar R, Musiyenko A, Oldenburg A, Adams B, Barik S: Post-translational generation of constitutively active cores from larger phosphatases in the malaria parasite, Plasmodium falciparum: implications for proteomics. BMC Mol Biol. 2004, 5: 6-10.1186/1471-2199-5-6.PubMed CentralView ArticlePubMedGoogle Scholar
- He CY, Shaw MK, Pletcher CH, Striepen B, Tilney LG, Roos DS: A plastid segregation defect in the protozoan parasite Toxoplasma gondii. EMBO J. 2001, 20: 330-339. 10.1093/emboj/20.3.330.PubMed CentralView ArticlePubMedGoogle Scholar
- Waller RF, McFadden GI: The apicoplast: a review of the derived plastid of apicomplexan parasites. Curr Issues Mol Biol. 2005, 7: 57-79.PubMedGoogle Scholar
- Fichera ME, Roos DS: A plastid organelle as a drug target in apicomplexan parasites. Nature. 1997, 390: 407-409. 10.1038/37132.View ArticlePubMedGoogle Scholar
- Boyce JM: MRSA patients: proven methods to treat colonization and infection. J Hosp Infect. 2001, 48: S9-S14. 10.1016/S0195-6701(01)90005-2.View ArticlePubMedGoogle Scholar
- Rock FL, Mao W, Yaremchuk A, Tukalo M, Crépin T, Zhou H, Zhang YK, Hernandez V, Akama T, Baker SJ, Plattner JJ, Shapiro L, Martinis SA, Benkovic SJ, Cusack S, Alley MRK: An Antifungal Agent Inhibits an Aminoacyl-tRNA Synthetase by Trapping tRNA in the Editing Site. Science. 2007, 316: 1759-1761. 10.1126/science.1142189.View ArticlePubMedGoogle Scholar
- Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997, 25: 3389-3402. 10.1093/nar/25.17.3389.PubMed CentralView ArticlePubMedGoogle Scholar
- Stalker J, Gibbins B, Meidl P, Smith J, Spooner W, Hotz HR, Cox AV: The Ensembl Web Site: Mechanics of a Genome Browser. Genome Res. 2004, 14: 951-955. 10.1101/gr.1863004.PubMed CentralView ArticlePubMedGoogle Scholar
- Wilson D, Pethica R, Zhou Y, Talbot C, Vogel C, Madera M, Chothia C, Gough J: SUPERFAMILY - Comparative Genomics, Datamining and Sophisticated Visualisation. Nucleic Acids Res. 2009, 37: 380-386. 10.1093/nar/gkn762.View ArticleGoogle Scholar
- Letunic I, Doerks T, Bork P: SMART 6: Recent updates and new developments. Nucleic Acids Res. 2008, 37: 229-232. 10.1093/nar/gkn808.View ArticleGoogle Scholar
- Bateman A, Birney E, Cerruti L, Durbin R, Etwiller L, Eddy SR, Griffiths-Jones S, Howe KL, Marshall M, Sonnhammer EL: The Pfam protein families database. Nucleic Acids Res. 2002, 30: 276-280. 10.1093/nar/30.1.276.PubMed CentralView ArticlePubMedGoogle Scholar
- Hughey R, Krogh A: Hidden Markov models for sequences analysis: Extension and analysis of the basic method. Computer Applications in the Biosciences. 1996, 12: 95-107.PubMedGoogle Scholar
- Szymanski M, Deniziak MA, Barciszewski J: Aminoacy-tRNA synthetases database. Nucleic Acids Res. 2001, 29: 288-290. 10.1093/nar/29.1.288.PubMed CentralView ArticlePubMedGoogle Scholar
- Claros MG, Vincens P: Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem. 1996, 241: 779-786. 10.1111/j.1432-1033.1996.00779.x.View ArticlePubMedGoogle Scholar
- Cokol M, Nair R, Rost B: Finding nuclear localization signals. EMBO reports. 2000, 1: 411-415. 10.1093/embo-reports/kvd092.PubMed CentralView ArticlePubMedGoogle Scholar
- Zuegge J, Ralph S, Schmuker M, McFadden GI, Schneider G: Deciphering apicoplast targeting signals - feature extraction from nuclear-encoded precursors of Plasmodium falciparum apicoplast proteins. Gene. 2001, 280: 19-26. 10.1016/S0378-1119(01)00776-4.View ArticlePubMedGoogle Scholar
- Irirzarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP: Exploration, normalization and summaries of high densities of oligonucleotide array probe level data. Biostatistics. 2003, 4: 249-264. 10.1093/biostatistics/4.2.249.View ArticleGoogle Scholar
- Troyanskaya O, Cantor M, Sherlock G: Missing value estimation method for DNA microarrays. Bioinformatics. 2001, 17: 520-525. 10.1093/bioinformatics/17.6.520.View ArticlePubMedGoogle Scholar
- Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994, 22: 4673-4680. 10.1093/nar/22.22.4673.PubMed CentralView ArticlePubMedGoogle Scholar
- Stéphane G, Franck L, Patrice D, Olivier G: PHYML Online--a web server for fast maximum likelihood-based phylogenetic inference. Nucleic Acids Res. 2005, W557-W559.Google Scholar
- Kumar S, Dudley J, Nei M, Tamura K: MEGA: A biologist-centric software for evolutionary analysis of DNA and protein sequences. Briefings in Bioinformatics. 2008, 9: 299-306. 10.1093/bib/bbn017.PubMed CentralView ArticlePubMedGoogle Scholar
- Renom MA, Stuart A, Fiser A, Sánchez R, Melo F, Sali A: Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct. 2000, 29: 291-325. 10.1146/annurev.biophys.29.1.291.View ArticleGoogle Scholar
- Laskowski RA, MacArthur MW, Moss DS, Thornton JM: PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst. 1993, 26: 283-291. 10.1107/S0021889892009944.View ArticleGoogle Scholar
- Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE: UCSF Chimera - A Visualization System for Exploratory Research and Analysis. J Comput Chem. 2004, 25: 1605-1612. 10.1002/jcc.20084.View ArticlePubMedGoogle Scholar
- DeLano WL: The PyMOL Molecular Graphics System. DeLano Scientific, San Carlos, CA, USA . 2002, [http://www.pymol.org]Google Scholar
- Lasonder E, Ishihama Y, Andersen JS, Vermunt AM, Pain A, Sauerwein RW, Eling WM, Hall N, Waters AP, Stunnenberg HG, Mann M: Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry. Nature. 2002, 419: 537-542. 10.1038/nature01111.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.