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Aminoacyl-Trna Synthetase Complexes: Molecular Multitasking Revealed Corinne D

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Aminoacyl-Trna Synthetase Complexes: Molecular Multitasking Revealed Corinne D REVIEW ARTICLE Aminoacyl-tRNA synthetase complexes: molecular multitasking revealed Corinne D. Hausmann1 & Michael Ibba1,2 1Department of Microbiology, The Ohio State University, Columbus, OH, USA; and 2Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA Correspondence: Michael Ibba, Department Abstract of Microbiology, The Ohio State University, 484 West 12th Avenue, Columbus, OH The accurate synthesis of proteins, dictated by the corresponding nucleotide 43210-1292, USA. Tel.: 1614 292 2120; sequence encoded in mRNA, is essential for cell growth and survival. Central to fax: 1614 292 8120; e-mail: [email protected] this process are the aminoacyl-tRNA synthetases (aaRSs), which provide amino acid substrates for the growing polypeptide chain in the form of aminoacyl-tRNAs. Received 29 February 2008; revised 21 April The aaRSs are essential for coupling the correct amino acid and tRNA molecules, 2008; accepted 24 April 2008. but are also known to associate in higher order complexes with proteins involved First published online June 2008. in processes beyond translation. Multiprotein complexes containing aaRSs are found in all three domains of life playing roles in splicing, apoptosis, viral DOI:10.1111/j.1574-6976.2008.00119.x assembly, and regulation of transcription and translation. An overview of the complexes aaRSs form in all domains of life is presented, demonstrating the Editor: Rafael Giraldo extensive network of connections between the translational machinery and cellular Keywords components involved in a myriad of essential processes beyond protein synthesis. aminoacyl-tRNA synthetase; translation; amino acid. adenosine. Once synthesized, aa-tRNAs are selectively bound Introduction by EF-1A in archaea and eukaryotes (homologous to the The faithful translation of mRNA into protein requires bacterial EF-Tu) as a ternary complex with GTP and ushered aminoacyl-tRNA synthetases (aaRSs), which provide the to the ribosome during protein synthesis. Eukaryotic aaRSs elongating polypeptide chain with amino acids in the form are distinguished by the presence of appended domains at of aminoacyl-tRNAs (aa-tRNA). The aaRSs are responsible either the N- or C-terminus, which are generally absent from for accurately attaching the correct amino acid onto the their bacterial/archaeal counterparts (Mirande, 1991). These cognate tRNA molecule in a two-step reaction. The amino appendages to the catalytic cores of several aaRSs are non- acid is first activated with ATP, forming an aminoacyl- catalytic and instead function to mediate protein–protein adenylate intermediate. Once activated, the amino acid is interactions or act as general RNA-binding domains (Cahuzac transferred to the 30 end of its corresponding tRNA molecule et al., 2000; Robinson et al., 2000; Guigou et al., 2004). to be used for protein synthesis. Although related by this An elaborate network of protein–protein interactions is common mechanism of aminoacylation, aaRSs are separated required for efficient translation in all domains of life. AaRSs into two classes (I and II) based on the structural topologies must correctly bind a diverse array of molecules to perform of their active sites (Cusack et al., 1990; Eriani et al., 1990). their essential function of aminoacylation, including ATP, Class I aaRSs are generally monomeric and composed of a amino acids, tRNAs, and in some cases other aaRSs. Also, Rossmann-nucleotide-binding fold, containing the highly several aaRSs associate with additional or auxiliary protein conserved sequence elements KMSKS and HIGH. Class I factors that are primarily used in cellular tasks beyond enzymes approach tRNA from the minor groove of the tRNA translation, expanding the repertoire of functions aaRSs acceptor stem, aminoacylating the terminal adenosine of the may pursue (Fig. 1). Although many of these associations tRNA molecule at the 20-OH position. Class II aaRSs are were first described in eukaryotic cells, numerous multi- generally multimeric enzymes that approach the major groove enzyme complexes containing aaRSs have recently been of their respective tRNAs, charging the 30-OH of the terminal identified in both bacteria and archaea (Table 1). FEMS Microbiol Rev 32 (2008) 705–721 c 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved 706 C.D. Hausmann & M. Ibba Soll,¨ 2005). To overcome this deficiency, bacterial ProRS forms stable interactions with YbaK, a free-standing homo- logue of the ProRS Ala-tRNAPro-editing domain (An & Musier-Forsyth, 2004, 2005; Ruan & Soll,¨ 2005). Stable ternary complex formation between bacterial ProRS, tRNAPro, and YbaK results in hydrolysis of mis- charged Cys-tRNAPro both in vitro and in vivo (An & Musier-Forsyth, 2005; Ruan & Soll,¨ 2005). YbaK, a general tRNA-binding protein, does not specifically recognize tRNAPro, necessitating protein interactions with ProRS for correct substrate binding. Interestingly, YbaK not only deacylates Cys-tRNAPro, but may also diminish the forma- tion of mischarged Cys-tRNAPro by ProRS, further guarding against the incorporation of noncognate amino acids into the growing polypeptide chain (An & Musier-Forsyth, 2005). In competition studies, YbaK was unable to compete with EF-Tu for Cys-tRNAPro, suggesting that YbaK hydro- lyzes mischarged tRNAs before their release from ProRS. Fig. 1. AaRSs impact a diverse range of functions throughout all The inability of YbaK alone to either specifically recognize domains of life. tRNAPro or to compete with EF-Tu for binding of the mischarged species means that complex formation between YbaK and ProRS is essential for efficient hydrolysis of Complexes in bacteria mischarged Cys-tRNAPro. Bacterial aaRSs are generally thought to function as stand- alone proteins to carry out the fundamental task of aminoa- Transamidosome (aspartyl-tRNA cylation. However, a handful of binary complexes comprised synthetase : amidotransferase) of one aaRS and a second protein factor have recently been While some mischarged aa-tRNAs are hydrolyzed by ap- discovered in bacteria, with one early report suggesting the pended or discrete editing domains, protein synthesis in formation of a higher order multi-aaRS complex (Harris, many bacterial species rely on the incorrect coupling of 1987). These binary complexes are involved in a diverse certain amino acid and tRNA pairs. Such is the case for the range of functions, from editing of misacylated tRNAs to synthesis of Asn-tRNAAsn and Gln-tRNAGln, which proceeds metabolite biosynthesis. via the specific mischarging of tRNAAsn and tRNAGln by aspartyl- and glutamyl-tRNA synthetases (AspRS and Prolyl-tRNA synthetase :YbaK GluRS), respectively (Schon et al., 1988; Feng et al., 2005; Accurate translation of the genetic code relies on the correct Bailly et al., 2007). The indirect synthesis of Asn-tRNAAsn pairing of amino acids with their cognate tRNAs. In order to requires a two-step reaction in which first a nondiscriminat- preserve the fidelity of protein synthesis, misactivated amino ing AspRS mischarges tRNAAsn with aspartic acid (Becker & acids and mischarged tRNAs must be efficiently hydrolyzed Kern, 1998; Tumbula-Hansen et al., 2002; Min et al., 2003; to avoid infiltration of the genetic code by noncognate Cardoso et al., 2006). The misacylated Asp-tRNAAsn is then amino acids (Baldwin & Berg, 1966; Eldred & Schimmel, bound by the GatCAB amidotransferase, which functions to 1972; Fersht & Dingwall, 1979; Kim et al., 1993; Schmidt & convert the aspartic acid moiety to asparagine in the Schimmel, 1994; Roy et al., 2004; Williams & Martinis, presence of an amide donor. Similarly, Gln-tRNAGln in 2006). This may be accomplished by discrete, free-standing bacteria and organelles is synthesized via an indirect path- editing proteins or by editing domains appended to the way, which requires misacylation of tRNAGln by GluRS and catalytic cores of aaRSs (Ahel et al., 2003; Wong et al., 2003; subsequent conversion to Gln-tRNAGln by the GatCAB Korencic et al., 2004; Fukunaga & Yokoyama, 2007a, b). amidotransferase (Curnow et al., 1998; Raczniak et al., Prolyl-tRNA synthetase (ProRS) is known to misactivate 2001; Salazar et al., 2001; Oshikane et al., 2006). The tRNAPro with alanine and cysteine (Ambrogelly et al., 2002; synthesis of Asn-tRNAAsn and Gln-tRNAGln via indirect An & Musier-Forsyth, 2005). Although most ProRS en- pathways is essential for those bacterial species whose zymes have editing domains that efficiently deacylate Ala- genomes do not code for asparaginyl- or glutaminyl-tRNA tRNAPro, ProRS is unable to clear Cys-tRNAPro (Beuning & synthetases (AsnRS or GlnRS, respectively), providing the Musier-Forsyth, 2001; An & Musier-Forsyth, 2005; Ruan & sole route for biosynthesis of these amino acid : tRNA pairs. c 2008 Federation of European Microbiological Societies FEMS Microbiol Rev 32 (2008) 705–721 Published by Blackwell Publishing Ltd. All rights reserved Aminoacyl-tRNA synthetase complexes 707 Table 1. aaRS-containing complexes in all three domains of life aaRS component(s) Accessory Domain (class) protein(s) Species Function References Bacteria ProRS (II) YbaK H. influenza; Hydrolysis of Cys-tRNAPro An & Musier-Forsyth (2004), E. coli Ruan & Soll¨ (2005) AspRS (II) GatCAB T. thermophilus Conversion of Asp-tRNAAsn Bailly et al. (2007) amidotransferase to Asn-tRNAAsn TrpRS (II) Nitric oxide D. radiodurans Nitration of tryptophan, Buddha et al. (2004a), Buddha et al. synthase producing 4-nitro-Trp (2004b), Buddha & Crane (2005) Archaea ProRS
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