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Unique Protein Architecture of Alanyl-Trna Synthetase for Aminoacylation, Editing, and Dimerization

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Unique Protein Architecture of Alanyl-Trna Synthetase for Aminoacylation, Editing, and Dimerization Unique protein architecture of alanyl-tRNA synthetase for aminoacylation, editing, and dimerization Masahiro Naganumaa, Shun-ichi Sekinea,b, Ryuya Fukunagaa,1, and Shigeyuki Yokoyamaa,b,2 aDepartment of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; and bRIKEN Systems and Structural Biology Center, Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Edited by Paul R. Schimmel, The Scripps Research Institute, La Jolla, CA, and approved April 6, 2009 (received for review February 17, 2009) Alanyl-tRNA synthetase (AlaRS) specifically recognizes the major nants of other aaRS–tRNA pairs. It was also striking that the identity determinant, the G3:U70 base pair, in the acceptor stem of predominant identity determinant of a tRNA exists in the tRNAAla by both the tRNA-recognition and editing domains. In this acceptor–stem duplex, rather than the anticodon and the dis- study, we solved the crystal structures of 2 halves of Archaeoglo- criminator base (9, 10). Actually, AlaRS can aminoacylate small, bus fulgidus AlaRS: AlaRS-⌬C, comprising the aminoacylation, isolated portions of tRNA, such as a ‘‘minihelix’’ and a ‘‘micro- tRNA-recognition, and editing domains, and AlaRS-C, comprising helix,’’ as long as they have the G3:U70 base pair (11). The the dimerization domain. The aminoacylation/tRNA-recognition G3:U70 base pair is considered to be recognized from the minor domains contain an insertion incompatible with the class-specific groove side (12, 13). tRNA-binding mode. The editing domain is fixed tightly via hydro- An E. coli AlaRS fragment comprising the aminoacylation and phobic interactions to the aminoacylation/tRNA-recognition do- tRNA-recognition domains (the N-terminal 461 residues) can mains, on the side opposite from that in threonyl-tRNA synthetase. specifically aminoacylate tRNAAla (1). The crystal structure of A groove formed between the aminoacylation/tRNA-recognition the corresponding fragment (AlaRS-N) from the bacterium domains and the editing domain appears to be an alternative Aquifex aeolicus was reported (14, 15). It revealed that AlaRS tRNA-binding site, which might be used for the aminoacylation does not dimerize through the aminoacylation domain, in con- and/or editing reactions. Actually, the amino acid residues required trast to the other class II aaRSs. The structures of amino acid- for the G3:U70 recognition are mapped in this groove. The dimer- and ATP-bound AlaRS-N revealed how the cognate alanine and ization domain consists of helical and globular subdomains. The the noncognate glycine and serine interact with the aminoacy- helical subdomain mediates dimerization by forming a helix– lation site. AlaRS is one of the aaRSs that use the proofreading loop–helix zipper. The globular subdomain, which is important for mechanism, in that mischarged products, such as Gly-tRNAAla the aminoacylation and editing activities, has a positively-charged and Ser-tRNAAla, are transferred to the editing domain, where face suitable for tRNA binding. the ester bond is hydrolyzed (2). A defect in the AlaRS editing activity causes cell death in the mouse nervous system (16). It was crystal structure ͉ dimerization domain ͉ aminoacyl-tRNA synthetase ͉ recently reported that the E. coli AlaRS editing domain pos- proofreading ͉ wobble base pair sesses a region, distinct from the N-terminal domains, that recognizes the G3:U70 base pair (17). Therefore, AlaRS may Ala minoacyl-tRNA synthetases (aaRSs) catalyze the ligation of transfer the acceptor stem of tRNA from the first binding site Acognate amino acids and tRNAs, and thus establish the in the aminoacylation domain to the second site in the editing genetic code in protein biosynthesis. They are modular proteins domain, in contrast to the other editing aaRSs (classes I and II), composed of an aminoacylation domain and a few additional which have been proposed to shuttle the flexible single-stranded domains for discrete functions, such as tRNA binding, oligomer- CCA terminus of the tRNA between the aminoacylation and ization, and amino acid proofreading (1, 2). The 20 aaRSs are editing catalytic sites (18–22). The C-terminal domain of AlaRS divided into 2 classes, I and II, based on the 2 unrelated types of is not only essential for the oligomerization, but also important BIOCHEMISTRY aminoacylation domains (3, 4). The aminoacylation reaction for the aminoacylation and editing reactions (17, 23). Small occurs at the catalytic site on the aminoacylation domain, and proteins homologous to the AlaRS editing domain, designated the reaction generally consists of 2 steps: the initial activation of AlaX, are found in many organisms (24, 25). They are active in Ala the amino acid with ATP to generate the aminoacyl-adenylate, the trans hydrolysis of misacylated tRNA in vitro (24). The Ala followed by the transfer of the aminoacyl moiety to the 3Ј end crystal structures of AlaX-S (specific to Ser-tRNA ) and Ala Ala of the tRNA. Although the aminoacylation is generally accurate, AlaX-M (specific to Ser-tRNA and Gly-tRNA ) from the several aaRSs cannot completely avoid the misactivation of a archaeon Pyrococcus horikoshii have been reported (26, 27). noncognate amino acid, when it is similar to the cognate one. To The structures of the editing and oligomerization domains, the solve this problem, these aaRSs use a proofreading mechanism, basis of oligomerization, and the domain arrangement in the in which the incorrect products are hydrolyzed at the active site full-length AlaRS have remained elusive. We previously suc- in the editing domain. ceeded in the crystallization of 2 fragments of AlaRS from the Alanyl-tRNA synthetase (AlaRS) is one of the class II aaRSs and consists of 4 domains: the N-terminal class II aminoacylation Author contributions: S.Y. designed research; M.N., S.S., and R.F. performed research; M.N., domain, the tRNA-recognition domain, the editing domain, and S.S., and S.Y. analyzed data; and M.N., S.S., and S.Y. wrote the paper;. the C-terminal oligomerization (dimerization or tetrameriza- The authors declare no conflict of interest. tion) domain (Fig. 1A) (1, 2). AlaRS occupies a special position This article is a PNAS Direct Submission. in the history of aaRS research. Escherichia coli AlaRS was Data deposition: The coordinates and structure factors have been deposited in the Protein among the first aaRSs that were cloned, sequenced, and char- Data Bank, www.pdb.org (PDB ID codes 2ZTG and 2ZVF). acterized genetically and biochemically (1, 5, 6). tRNAAla con- 1Present address: Department of Biochemistry and Molecular Pharmacology, University of serves a unique G3:U70 wobble base pair in the acceptor stem, Massachusetts Medical School, Worcester, MA 01605. and this base pair dictates the tRNA identity toward AlaRS 2To whom correspondence should be addressed. E-mail: [email protected]. (7, 8). This remarkable finding, that a small number of nucleo- u-tokyo.ac.jp. tide residues serve as the predominant determinant for the This article contains supporting information online at www.pnas.org/cgi/content/full/ tRNA identity, accelerated the search for the identity determi- 0901572106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0901572106 PNAS ͉ May 26, 2009 ͉ vol. 106 ͉ no. 21 ͉ 8489–8494 Downloaded by guest on October 6, 2021 A Aminoacylation tRNA recognition Editing Oligomerization A B AlaRS 1 906 AddA1 InsB/E1 AlaRS-ΔC 1 739 AlaRS-C 736 906 InsA1 B Aminoacylation Editing InsB/E2 InsA1 Linker N motif1 AddA1 β barrel InsA2 Mid2 Mid2 A.fulgidus A.aeolicus Fig. 2. The aminoacylation and tRNA-recognition domains. (A) The amino- acylation and tRNA-recognition domains of A. fulgidus AlaRS, colored as in InsA2 C Fig. 1B, are shown. (B) The A. aeolicus AlaRS-N structure, shown in the same orientation. The 2 regions missing in A. fulgidus (InsB/E1 and InsB/E2) are colored brown, and Mid2 is shown in gold. Editing core Mid1 AlaRS independently recognize the G3:U70 base pair of Mid2 Helix-loop tRNAAla. tRNA recognition Results C Structure Determination. A. fulgidus AlaRS is a homodimer of 906 C amino acid residue polypeptides (23). It was genetically divided into 2 parts, AlaRS-⌬C (residues 1–739) and AlaRS-C (residues 736–906) (23), and both structures were solved (Table S1). Globular subdomains AlaRS-⌬C is composed of the class-II specific aminoacylation domain, the tRNA-recognition domain, and the editing domain. The structure of AlaRS-⌬C complexed with an alanyl-adenylate C analog, 5Ј-O-[N-(L-alanyl)sulfamoyl] adenosine (Ala-SA), was determined at 2.2 Å (Fig. 1B). The crystallographic asymmetric unit contained 1 AlaRS-⌬C molecule. The refined model has R and Rfree factors of 21.5% and 26.4%, respectively. AlaRS-C comprises the dimerization domain, and its structure was deter- N mined at 3.2 Å (Fig. 1C). Two AlaRS-C molecules form a Helical subdomains homodimer, and there are 4 dimers in the asymmetric unit. The N refinement converged to R and Rfree factors of 20.5% and 27.6%, respectively (Table S1). Fig. 1. The structures of AlaRS-⌬C and AlaRS-C. (A) Domain organizations of A. fulgidus AlaRS, AlaRS-⌬C, and AlaRS-C. Shown are the aminoacylation The Aminoacylation Domain. The A. fulgidus AlaRS-⌬C structure domain (green), Mid1 (blue) and Mid2 (cyan) in the tRNA-recognition domain, revealed the aminoacylation domain (residues 1–257), composed ␤ the -barrel (yellow) and editing-core (orange) subdomains in the editing of a central antiparallel ␤-sheet (␤1–␤8 and ␤10) and 5 ␣-helices domain, and the helical (midnight blue) and globular (light blue) subdomains ␣ ␣ in the dimerization domain. (B) A ribbon representation of AlaRS-⌬C. The ( 1– 5), which is typical of the class-II aaRSs. It is superposable model is colored as in A, and the N-terminal addition (AddA1) and insertions on that of A.
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