An emergency brake for protein synthesis

Abstract

The integrated stress response is able to rapidly shut down the synthesis of proteins in eukaryotic cells.

Keywords: ISR; S. cerevisiae; biochemistry; chromosomes; eIF2; eIF2B; genes; protein interactions; translational control.

Figure 1.. How translation can be stopped and started during protein synthesis.

Three of the main players in the control of translation act like the clutch (eIF2), brake (eIF2B) and accelerator (eIF5) in a car. (A) Once the translation of an mRNA molecule has started, a complex containing eIF2-GDP (which is inactive) and eIF5 leaves the ribosome. (B) eIF2B then out-competes eIF5 and mediates the exchange of GDP and GTP to yield eIF2-GTP (which is active). (C) eIF2-GTP and initiator Met-tRNA then form a ternary complex, which is stabilized by eIF5, and a new cycle of translation can begin. (D) Sometimes a cell has to reduce protein synthesis in response to stress or other factors, and this response starts with the phosphorylation (P) of a specific amino acid (Ser51) in eIF2. (E) This phosphorylation has important consequences: eIF2B is unable to mediate the exchange of GDP and GTP, and translation cannot proceed. (F, G) Jennings et al. show that if the phosphorylation of Ser51 occurs on eIF2 present in an existing ternary complex, the phosphoryl group allows eIF2B to out-compete eIF5: this means that eIF5 cannot stabilize the ternary complex, so the complex falls apart and translation is stopped completely.