Role of D-aminoacyl-tRNA deacylase beyond chiral proofreading as a cellular defense against glycine mischarging by AlaRS

摘要

Proteins are made up of many different building blocks called amino acids, which are linked together in chains. The exact order of amino acids in a protein chain is important for the protein to work properly. When a cell makes proteins, molecules known as transfer ribonucleic acids (or tRNAs for short) bind to specific amino acids to guide them to the growing protein chains in the correct order. Most amino acids – except one called glycine – have two forms that are mirror images of one another, known as left-handed (L-amino acids) and right-handed (D-amino acids). However, only L-amino acids and glycine are used to make proteins. This is because of the presence of multiple quality control checkpoints in the cell that prevent D-amino acids from being involved. One such checkpoint is an enzyme called D-amino acid deacylase (DTD), which removes D-amino acids that are attached to tRNAs. Other enzymes are responsible for linking a particular amino acid to its correct tRNA. Along with mistaking D-amino acids for L-amino acids, these enzymes can also make errors when they have to distinguish between amino acids that are similar in shape and size. For example, the enzyme that attaches L-alanine to its tRNA can also mistakenly attach larger L-serine or smaller glycine to it instead. Previous research has shown that attaching L-serine to this tRNA can lead to neurodegeneration in mice, whereas attaching glycine does not seem to cause any harm. It is not clear why this is the case. Pawar et al. investigated how incorrectly attaching glycine or L-serine to the tRNA that usually binds to L-alanine affects a bacterium called Escherichia coli. The experiments show that, if the mistake is not corrected, glycine can be just as harmful to the cells as L-serine. The reason that glycine appears to be less of a problem is that the DTD enzyme is able to remove glycine, but not L-serine, from the tRNA. Further experiments show that DTD can play a similar role in a variety of organisms from bacteria to mammals. The findings of Pawar et al. extend the role of DTD beyond preventing D-amino acids from being incorporated into proteins. The next step is to understand the role of this enzyme in humans and other multicellular organisms, especially in the context of nerve cells, where it is present at high levels.