Translational Control / Regulation of eIF2 Interactive Pathway
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-tRNAi 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 with the help of the GTPase activating protein eIF5 and dissociates from the mRNA, permitting the binding of the 60S ribosomal subunit and elongation of the polypeptide chain. eIF2 remains bound to GDP in the presence of eIF5 acting as a GDI. To permit another round of initiation, eIF2B must act as both a GDI displacement factor (GDF) and a guanine exchange factor (GEF) to allow exchange of GDP for GTP on eIF2. This step is tightly regulated, and phosphorylation of eIF2α by a diverse family of four stress activated kinases—PKR (dsRNA), PERK (ER stress), GCN2 (amino acid starvation), and HRI (heme deficiency)—prevents nucleotide exchange by causing eIF2 to act as a dominant negative complex to sequester eIF2B. The resulting increase in eIF2α-GDP limits the availability of the ternary complex and causes a decrease in global protein synthesis and an enhancement of the translation of specific stressrelated mRNA transcripts, such as the transcription factors ATF-4 and CHOP.
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We would like to thank Rachel Wolfson and Prof. David Sabatini, Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, for reviewing this diagram.
created January 2002
revised June 2014