Breakthroughs and Views
Molecular network and functional implications of macromolecular tRNA synthetase complex

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Abstract

Understanding the complex network and multi-functionality of proteins is one of the main objectives of post-genome research. Aminoacyl-tRNA synthetases (ARSs) are the family of enzymes that are essential for cellular protein synthesis and viability that catalyze the attachment of specific amino acids to their cognate tRNAs. However, a lot of evidence has shown that these enzymes are multi-functional proteins that are involved in diverse cellular processes, such as tRNA processing, RNA splicing and trafficking, rRNA synthesis, apoptosis, angiogenesis, and inflammation. In addition, mammalian ARSs form a macromolecular complex with three auxiliary factors or with the elongation factor complex. Although the functional meaning and physiological significance of these complexes are poorly understood, recent data on the molecular interactions among the components for the multi-ARS complex are beginning to provide insights into the structural organization and cellular functions. In this review, the molecular mechanism for the assembly and functional implications of the multi-ARS complex will be discussed.

Section snippets

Aminoacyl-tRNA synthetase

Specific recognition between ARSs and tRNAs is critical for the precise translation of the genetic code into the protein sequence. In spite of their common function in protein synthesis, ARSs have been diversified in their molecular weight, primary sequence, and quaternary structure. Based on amino acid sequence alignments and structural features, ARSs have been divided into two classes (Table 2) [14], [15], [16]. The class I synthetases are generally monomers or dimers and share two consensus

Complex formation of aminoacyl-tRNA synthetases

ARSs can also be distinguished, based on their property to form a macromolecular complex. A primitive form of these complexes is present in yeast. The yeast ARS complex is composed of glutamyl- (ERS) and methionyl-tRNA synthetases (MRS), and the non-enzyme component called Arc1p which is homologous to mammalian p43 that is also bound to the multi-ARS complex [17]. Due to its relative simplicity, its structural organization and function have been well understood [18]. This complex is stable in

Structural organization of aminoacyl-tRNA synthetase complex

Although the multi-ARS complex has been known for the last two decades, the structural organization and functional significance of this multi-enzyme complex are not yet completely delineated. Mammalian ARSs have extra peptide appendices that are absent in their prokaryotic counterparts. Because prokaryotic ARSs exist as free forms and do not form macromolecular complexes, eukaryotic extra peptide appendices were considered as responsible for the molecular assembly of the enzymes or in other

Multi-functionality of ARS and functional implications for the complex formation of ARSs

Recent evidence showed that the components of the ARS complex participate in various biological processes in addition to protein synthesis (Fig. 3). Human QRS was shown to have an anti-apoptotic function [50]. QRS specifically interacts with the apoptosis signal-regulating kinase 1 (ASK1) in a glutamine-dependent manner and inhibits the ASK1-mediated apoptosis by inhibiting the kinase activity of ASK1. Since Fas-induced ASK1 and c-Jun N-terminal kinase (JNK) activities are inhibited by the

Conclusions and future prospects

Since many of the complex-forming ARSs are active in the free state in vitro, it is clear that the complex formation is not essential for their catalytic activity. In the multi-ARS complex, the aminoacylation reactions that are catalyzed by the component enzymes would proceed in parallel. Considering the size of the substrate tRNAs, a significant traffic jam during the entrance and exit of the substrates and steric hindrance between them are expected within the complex. Also, the mouse

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