to see a detailed, interactive version of this map NOTE: PathFinder requires the Flash plug-in for proper viewing. It will launch in a separate pop-up window, please turn off any pop-up blockers for this web site. Copyright ©2006 ProteinLounge.com

 eIF2 Pathway

Initiation of protein synthesis (translation) in eukaryotes requires the formation of an 80S complex in which initiator Met-tRNA (Meti-tRNA) is based paired with an mRNA AUG start codon in the P-site of the ribosome. The assembly of an active translation complex requires the pre-assembly of a 43S preinitiation complex and an initiation-factor complex. The 43S preinitiation complex is assembled by the association of the 40S ribosomal subunit with a ternary complex (TC) composed of Met_i-tRNA and GTP-charged eIF2. This assembly is promoted by eIF1, eIF1A factors and the eIF3 complex. The assembled preinitiation complex interacts with and scans mRNA to pair Met_i-tRNA with the AUG start codon. This process is facilitated by the initiation-factor complex composed of eIF4F (eIF4A-eIF4E-eIF4G), poly(A)-binding protein, mRNA and eIF3. AUG recognition triggers eIF5 stimulated GTP hydrolysis and ejection of GDP-charged eIF2 from the ribosome.

Eukaryotic initiation factor 2 (eIF2) is a heterotrimer composed of eIF2alpha (eIF2α), eIF2beta (eIF2β) and eIF2gamma (eIF2γ). The eIF2betagamma (eIF2βγ) dimer is active, but very slow compared to the eIF2alphabetagamma (eIF2αβγ) complex. The delivery of Meti-tRNA to the AUG start codon in the translation initiation complex requires the hydrolysis of GTP associated with eIF2. Eucaryotic IF2B is a guanine nucleotide exchange factor (GEF) that recharges GDP-charged eIF2 with GTP.

The replacement of GDP with GTP on eIF2 by eIF2B is an important factor in the regulation of protein synthesis initiation. Regulation of the initiation of translation at the level of eIF2 involves two phosphorylation cycles; one involving a subunit of eIF2 (eIF2alpha) and one involving a subunit of eIF2B (eIF2Bepsilon). IF2B is a heteropentameric protein whose activity is controlled by phosphorylation (inactivation) and dephosphorylation of its eIF2Bepsilon subunit, the GEF subunit. Constitutively active glycogen synthetase 3β (GSK3β) is a major kinase that phosphorylates and inactivates eIF2Bepsilon. Growth factor and cytokine receptors that activate the PI3-K/PDK/Akt pathway phosphorylate and inactivate GSK3β. They sustain protein synthesis. Initiation of translation can also be interrupted by phosphorylation of eIF2alpha. Phosphorylation of eIF2alpha makes it an inhibitor of eIF2B function. It prevents dissociation of the eIF2.GDP complex from the initiation complex and interferes with eIF2B interactions with trimeric eIF2. Protein synthesis inhibition at the level of eIF2alpha phosphorylation is linked to a variety of cell stress signaling pathways via specific kinases: DAI and PKR are sensors of viral infection; HRI is a sensor of heme-deficiency; PERK is a sensor of endoplasmic-reticulum (ER) stress; and GCN2, is a sensor of amino acid deficiency. Phosphorylation of eIF2 reduces, but does not completely shut down global translation. IF2alpha phosphorylation induces changes in translation of specific mRNAs that code proteins that help it cope with stress.