Regulation of eukaryotic translation by the RACK1 protein: a platform for signalling molecules on the ribosome

Abstract

The receptor for activated C-kinase (RACK1) is a scaffold protein that is able to interact simultaneously with several signalling molecules. It binds to protein kinases and membrane-bound receptors in a regulated fashion. Interestingly, RACK1 is also a constituent of the eukaryotic ribosome, and a recent cryo-electron microscopy study localized it to the head region of the 40S subunit in the vicinity of the messenger RNA (mRNA) exit channel. RACK1 recruits activated protein kinase C to the ribosome, which leads to the stimulation of translation through the phosphorylation of initiation factor 6 and, potentially, of mRNA-associated proteins. RACK1 therefore links signal-transduction pathways directly to the ribosome, which allows translation to be regulated in response to cell stimuli. In addition, the fact that RACK1 associates with membrane-bound receptors indicates that it promotes the docking of ribosomes at sites where local translation is required, such as focal adhesions.

Figure 1

Position of receptor for activated C-kinase (RACK1) on the ribosome and its putative interactions with signalling molecules. (A) Cryo-electron microscopy map of 80S ribosomes from Saccharomyces cerevisiae showing the localization of RACK1 (red) on the small subunit (yellow). The mRNA exit channel is indicated by an arrow. (B–D) Schematic illustrations of RACK1 (red) bound to regulatory molecules on the ribosome in the vicinity of the mRNA (pink). (B) Protein kinase C (PKC; light blue) bound to ribosomes in the proximity of mRNA-associated proteins, such as initiation factor eIF4E (grey). (C) RACK1 bound to an mRNA-specific binding protein, such as Scp160p (grey) associated with mRNA. (D) Ribosomes recruited to sites of attachment through an interaction between integrin-β (dark brown) and RACK1. The illustrations of bound mRNA (pink), tRNA (green) and elongation factor 2 (eEF2; orange) in the intersubunit cleft show that translation could proceed while RACK1 interacts with the receptor.

Dr Nissen is the recipient of an EMBO Young Investigator Award