Introduction: tRNA Synthetases: Precise translation machines

The aminoacyl-tRNA synthetases (AARSs) are key proteins involved in the translation machinery in living organisms; it is not surprising, therefore, that these enzymes are found in all three domains of life. There are twenty specific tRNA synthetases (one for each amino acid), although not all organisms contain the full set. Studying the function, structure, and evolution of these proteins remains an area of intense interest as, in addition to being a major constituent of the translation process, these proteins are also believed to contain vital information spanning the evolution of life from the ancient "RNA world" to the modern form of life.

Figure 1:The reaction catalyzed by the aminoacyl tRNA synthetases (aa could be any amino acid).

The AARSs are responsible for loading the twenty different amino acids onto the cognate tRNA during protein synthesis (see Figure 1). Each AARS is a multidomain protein consisting of (at least) a catalytic domain and an anticodon binding domain. In all known cases, the synthetases divide into class I or class II types; class I AARSs exemplify the basic Rossmann fold, while class II AARSs exhibit a fold that is unique to them and biotin synthetase holoenzyme. Additionally, some of the AARSs, for example aspartyl-tRNA synthetase, have an "insert domain" within their catalytic domain (see Figure 2). Recognition of the tRNA molecule is typically performed by the anticodon domain, however residues that have degenerate codons (e.g. serine has six different codons) have been found to exploit other features in the tRNA for recognition (e.g. the acceptor arm or the so-called discriminator base). These molecular machines operate with remarkable precision, making only one mistake in every 10,000 translations. The intricate architecture of specific tRNA synthetases helps to discriminate against mis-coding.

Figure 2: A snapshot of AspRS-tRNA aspartyl-adenylate complex (from E. Coli) in the active form. Note the anticodon binding domain (orange), the insertion domain (pink), and the catalytic domain (blue). tRNA is docked to AspRS, and the catalytic active site is highlighted within the catalytic domain (red bubble); the aspartyl-adenylate substrate is shown in space-filling representation. The residues involved in specific base recognition on the tRNA are also highlighted within the anticodon binding domain (green bubble). Note that specific contacts between the tRNA and Asp-RS allow for strategic positioning of the tRNA relative to the enzyme.