Translational Control / Regulation of eIF2
Pathway Description:The eIF2 initiation complex integrates a diverse array of stress-related signals to regulate both global and specific mRNA translation. Under permissive conditions, eIF2 binds GTP and Met-tRNA to form the ternary complex (TC), which then associates with the 40S ribosomal subunit, eIF1, eIF1A, eIF5, and eIF3 to form the 43S pre-initiation complex (PIC). The 43S PIC scans the mRNA UTR for an AUG start codon. Upon AUG recognition, eIF2 hydrolyzes GTP to GDP and dissociates from the mRNA, permitting the binding of the 60S ribosomal subunit and elongation of the polypeptide chain. eIF2 is unable to participate in another round of initiation until GDP is exchanged for GTP, a reaction catalyzed by the guanine nucleotide exchange factor (GEF) eIF2B. This step is tightly regulated, and phosphorylation of eIF2α by a diverse family of four stressactivated kinases—PKR (dsRNA), PERK (ER stress), GCN2 (amino acid starvation), and HRI (heme deficiency)—prevents nucleotide exchange. An increase in eIF2α-GDP limits the availability of the ternary complex and causes a decrease in global protein synthesis while enhancing the translation of specific stress-related mRNA transcripts, such as the transcription factor ATF-4.
- Hinnebusch AG (2011) Molecular mechanism of scanning and start codon selection in eukaryotes. Microbiol. Mol. Biol. Rev. 75(3), 434–67, first page of table of contents.
- Raven JF, Koromilas AE (2008) PERK and PKR: old kinases learn new tricks. Cell Cycle 7(9), 1146–50.
- Schmitt E, Naveau M, Mechulam Y (2010) Eukaryotic and archaeal translation initiation factor 2: a heterotrimeric tRNA carrier. FEBS Lett. 584(2), 405–12.
- Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34(Pt 1), 7–11.
We would like to thank Carson Thoreen and Prof. David Sabatini, Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, for reviewing this diagram.
created January 2002
revised November 2012