Assembly of the Human Multi-tRNA Synthetase Complex Through Leucine Zipper Motifs.

Aminoacyl-tRNA synthetases (ARSs) are responsible for the ligation of amino acids to their cognate tRNAs. In human, nine ARSs form a multi-tRNA synthetase complex (MSC) with three ARS-interacting multifunctional proteins (AIMPs). Among the components of MSC, arginyl-tRNA synthetase 1 (RARS1) and two AIMPs (AIMP1 and AIMP2) have leucine zipper (LZ) motifs, which they utilize for their assembly in an MSC. RARS1 and AIMP1 have two LZ motifs (LZ1 and LZ2) in their N-terminus, respectively, while AIMP2 has one LZ motif between its lysyl-tRNA synthetase 1 (KARS1)-binding motif and glutathione transferase-homology domain, which links aspartyl-tRNA synthetase 1 (DARS1). Although the interaction mode between AIMP1 and RARS1, which also binds glutaminyl-tRNA synthetase 1 (QARS1), has been revealed, the mode in the presence of AIMP2 is still ambiguous since AIMP2 is known to not only bind to AIMP1 but also form a homodimer through its LZ. Here, we determined a crystal structure of the LZ complex of AIMP1 and AIMP2 and revealed the interaction mode of a heterotrimeric complex of RARS1, AIMP1, and AIMP2. The complex is established by a three-stranded coiled-coil structure with RARS1 LZ1, AIMP1 LZ1, and AIMP2 LZ and is completed with a two-stranded coiled-coil structure of RARS1 LZ2 and AIMP1 LZ2. In the human MSC, this heterotrimeric complex of RARS1, AIMP1, and AIMP2 allows for a subcomplex of fourteen protein molecules, in which two QARS1-RARS1-AIMP1-AIMP2-2 × KARS1 complexes are linked separately to a dimeric DARS1.