Abstract
Many multicomponent protein complexes mediating diverse cellular processes are assembled through scaffolds with specialized protein interaction modules. The multi-tRNA synthetase complex (MSC), consisting of nine different aminoacyl-tRNA synthetases and three non-enzymatic factors (AIMP1-3), serves as a hub for many signaling pathways in addition to its role in protein synthesis. However, the assembly process and structural arrangement of the MSC components are not well understood. Here we show the heterotetrameric complex structure of the glutathione transferase (GST) domains shared among the four MSC components, methionyl-tRNA synthetase (MRS), glutaminyl-prolyl-tRNA synthetase (EPRS), AIMP2 and AIMP3. The MRS-AIMP3 and EPRS-AIMP2 using interface 1 are bridged via interface 2 of AIMP3 and EPRS to generate a unique linear complex of MRS-AIMP3:EPRS-AIMP2 at the molar ratio of (1:1):(1:1). Interestingly, the affinity at interface 2 of AIMP3:EPRS can be varied depending on the occupancy of interface 1, suggesting the dynamic nature of the linear GST tetramer. The four components are optimally arranged for maximal accommodation of additional domains and proteins. These characteristics suggest the GST tetramer as a unique and dynamic structural platform from which the MSC components are assembled. Considering prevalence of the GST-like domains, this tetramer can also provide a tool for the communication of the MSC with other GST-containing cellular factors.
Highlights
GST domains have been found in diverse proteins involved in translational systems
The mixture of full-length methionyl-tRNA synthetase (MRS), His-EPRSGST4, His-AIMP3, and HisAIMP2GST2 was eluted from a gel filtration column as a single peak at a molecular size of around 290 kDa, the size predicted for a 1:1:1:1 tetrameric complex of the four proteins (Fig. 8E), suggesting that the GST tetramer can be formed with full-length proteins
We showed that the four different GST domains of multi-tRNA synthetase complex (MSC) components can assemble together to form multisubunit complexes in an orderly fashion
Summary
GST domains have been found in diverse proteins involved in translational systems. Results: Four GST domains from human methionyl-tRNA synthetase, glutaminyl-prolyl-tRNA synthetase, ARS-interacting multifunctional protein (AIMP) 2, and AIMP3 are complexed in an ordered fashion. The multi-tRNA synthetase complex (MSC), consisting of nine different aminoacyl-tRNA synthetases and three non-enzymatic factors (AIMP1–3), serves as a hub for many signaling pathways in addition to its role in protein synthesis. The four components are optimally arranged for maximal accommodation of additional domains and proteins These characteristics suggest the GST tetramer as a unique and dynamic structural platform from which the MSC components are assembled. Human multi-tRNA synthetase complex (MSC) is a macromolecular protein complex consisting of nine different ARSs and three ARS-interacting multifunctional proteins (AIMPs) [8]. As system complexity is accreted, several different domains have been recruited at one or both ends of the ARS catalytic domains [10] These acquired domains appear to provide flexibility and efficiency in catalysis and in protein synthesis and other signaling pathways. We present the heterotetrameric GST complex as a novel dynamic molecular framework to bring MSC components together
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