Architecture and Metamorphosis

Abstract

When compared to other conserved housekeeping protein families, such as ribosomal proteins, during the evolution of higher eukaryotes, aminoacyl-tRNA synthetases (aaRSs) show an apparent high propensity to add new sequences, and especially, new domains. The stepwise emergence of those new domains is consistent with their involvement in a broad range of biological functions beyond protein synthesis, and correlates with the increasing biological complexity of higher organisms. The new domains have been extensively characterized based on their evolutionary origins and their sequence, structural and functional features. While some of the domains are uniquely found in aaRSs and may have originated from nucleic acid binding motifs, others are common domain modules mediating protein-protein interactions that play a critical role in the assembly of the multi-synthetase complex (MSC). Interestingly, the MSC has emerged from a miniature complex in yeast, to a large, stable complex in insects to humans. The human MSC consists of 9 aaRSs (LysRS, ArgRS, GlnRS, AspRS, MetRS, IleRS, LeuRS and GluProRS) and 3 scaffold proteins (AIMP1/p43, AIMP2/p38 and AIMP3/p18), and has a molecular weight of 1.5 million Da. The MSC has been proposed to have a functional dualism: both facilitating protein synthesis and serving as a reservoir of non-canonical functions associated with its synthetase and non-synthetase components. Importantly, domain additions and functional expansions are not limited to the components of the MSC and are found in almost all aaRS proteins. From a structural perspective, multi-functionalities are represented by multiple conformational states. In fact, alternative conformations of aaRSs have been generated by various mechanisms from proteolysis to alternative splicing and posttranslational modifications, as well as by disease-causing mutations. Therefore, the metamorphosis between different conformational states is connected to the activation and regulation of the novel functions of aaRSs in higher eukaryotes.

Identification and Characterization of Potential Biomarkers by Quantitative Tissue Proteomics of Primary Lung Adenocarcinoma

“…In addition to serving this canonical function, higher eukaryotic ARSs have been implicated in a variety of noncanonical functions, including inflammation (38), angiogenesis (39), translation regulation (40), gene-specific translational silencing (41), apoptosis and angiogenesis (40 -45). Specifically, recent studies reported that ARSs are implicated in tumorigenesis through the interactions between different regulators and new domains of the ARSs (46). NARS, a class II ARS, was identified as an up-regulated protein in early-stage tumor tissues in this study.…”

Exploring the evolutionary diversity and assembly modes of multi‐aminoacyl‐tRNA synthetase complexes: Lessons from unicellular organisms

“…Leucine zipper (LZ) are also involved for the formation of complexes in higher eukaryotes but have not yet been found in aaRSs from lower eukaryotes and are therefore not described in this section. UNE‐X domains, unique domains specific to each aaRS, are not described in this section because they are not always protein‐ or RNA‐binding domains [72].…”

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

“…1A). These GST domains display strong homology to the GST domain of elongation factor eEF1B␥, which belongs to the theta class (4,5). Sequence alignment of the domains reveals that the GST-C subdomains are similar in size and well conserved in sequence, especially the residues involved in stabilizing the helical bundle structure, whereas GST-N subdomains are less conserved in size and sequence (Fig.…”

“…Among ARSs, GST homologs are found in methionyl-tRNA synthetase (MRS) from yeast to human and are involved in MRS catalysis (6). Mammalian valyl-tRNA synthetase, glutaminylprolyl-tRNA synthetase (EPRS), the largest isoform of human cysteinly tRNA synthetase, and glutamyl-tRNA synthetase (ERS) in some species, also contain a GST domain located in their N-terminal regions (5,7). Although the functional impli-cations of these embedded GST domains vary, they appear to play roles in protein assembly and folding.…”

“…Throughout evolution, GST structures have spread into different proteins (3), including aminoacyltRNA synthetases (ARSs) 3 and other translational factors (4,5). Among ARSs, GST homologs are found in methionyl-tRNA synthetase (MRS) from yeast to human and are involved in MRS catalysis (6).…”