Structure of the ArgRS–GlnRS–AIMP1 complex and its implications for mammalian translation

Abstract

In higher eukaryotes, one of the two arginyl-tRNA synthetases (ArgRSs) has evolved to have an extended N-terminal domain that plays a crucial role in protein synthesis and cell growth and in integration into the multisynthetase complex (MSC). Here, we report a crystal structure of the MSC subcomplex comprising ArgRS, glutaminyl-tRNA synthetase (GlnRS), and the auxiliary factor aminoacyl tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1)/p43. In this complex, the N-terminal domain of ArgRS forms a long coiled-coil structure with the N-terminal helix of AIMP1 and anchors the C-terminal core of GlnRS, thereby playing a central role in assembly of the three components. Mutation of AIMP1 destabilized the N-terminal helix of ArgRS and abrogated its catalytic activity. Mutation of the N-terminal helix of ArgRS liberated GlnRS, which is known to control cell death. This ternary complex was further anchored to AIMP2/p38 through interaction with AIMP1. These findings demonstrate the importance of interactions between the N-terminal domains of ArgRS and AIMP1 for the catalytic and noncatalytic activities of ArgRS and for the assembly of the higher-order MSC protein complex.arginyl-tRNA synthetase | multisynthetase complex | crystal structure | AIMP1 | glutaminyl-tRNA synthetase

Assembly of Multi-tRNA Synthetase Complex via Heterotetrameric Glutathione Transferase-homology Domains

“…Because PRS is covalently linked in EPRS and DRS tightly binds AIMP2 (36,37), the presence of the two homodimers, PRS and DRS, suggests duplication of the MRS-AIMP3-ERPS-AIMP2 complex in an MSC. The ternary complex of QRS-AIMP1-RRS also has the potential to form a hexamer consisting of homodimers of each component (32). This subcomplex could be symmetrically duplicated and the stoichiometry of KRS: (AIMP2:AIMP1:DRS:ERPS:RRS):(MRS:AIMP3:QRS) would be 4:(2):(2).…”

“…The dynamic affinity between AIMP3 and EPRS GST supports the release of the two components from the MSC. QRS is also weakly bound to MSC via its N-terminal helical interaction with the long helix of AIMP1 (32). Thus, linkage of the MSC subcomplex appears to accommodate both possible stoichiometries of the components.…”

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

“…AIMP1 is a non-enzymatic component of the MSC that mainly associates with RRS, QRS, and another non-enzymatic component, AIMP2, within the complex [42]. Extracellularly, AIMP1 activates innate immune cells such as macrophages and monocytes to produce inflammatory cytokines through MAPK signaling [43] and induces maturation of BMDCs [44].…”

Oncogenic Mutation of AIMP2/p38 Inhibits Its Tumor-Suppressive Interaction with Smurf2

“…AIMP2 serves as a scaffold protein interacting with multiple components of MSC (13,24), and its presence is important for the stability and assembly of the whole complex (28). Recently, crystal structures of KRS binding the N-terminus of AIMP2 (25) and AIMP1 forming a complex with RRS (arginyl-tRNA synthetase) and QRS (glutaminyl-tRNA synthetase) were revealed (29). As AIMP1 is anchored to AIMP2 via coiled-coil interaction of leucine zipper (26), RRS and QRS may be located proximal to AIMP2.…”