Schematic of a ribosome showing the P-stalk (pink). Image credit: Harding et al. (CC BY 4.0)
Often thought of as “workhorse” molecules, proteins take part in almost every structure and activity in a living cell. They are constructed from smaller building blocks called amino acids by molecular machines called ribosomes. Each cell needs a constant supply of amino acids to make new proteins. If cells are running low on amino acids, they can change their internal biochemistry to use amino acids more economically. GCN2 is one protein that helps activate these biochemical changes, but it was unclear how a shortage of amino acids could activate GCN2.
Earlier in 2019, researchers reported that, in a test tube at least, isolated ribosomes could themselves activate GCN2. They also identified a part of the ribosome called the P-stalk as playing an important role in the interaction. Now, Harding et al. – who include some of the researchers involved in the earlier study – explore the activation of GCN2 further, but this time based on experiments with mammalian cells.
First, a genetic screen was conducted to identify genes that if mutated specifically prevented the activation of GCN2 in cells that were starved of amino acids. This screen identified a few genes, several of which are involved in creating the P-stalk of the ribosome. By isolating the mutant ribosomes from these cells and studying them in the laboratory, Harding et al. then showed that these ribosomes are unable to activate GCN2.
These findings confirm that the P-stalk of the ribosome plays an essential role in activating GCN2 in response to a shortage of amino acids. They shed light on a fundamental biological system, and further work will undoubtedly seek to uncover the details of the process by which GCN2 is activated.
