eIF2GTPMettRNAi

eIF2GTPMettRNAi refers to the eIF2-GTP-Met-tRNAi ternary complex, a central component of eukaryotic translation initiation. This complex comprises the eIF2 guanine nucleotide-binding protein bound to GTP and the initiator methionyl-tRNA (Met-tRNAi). When loaded with GTP, eIF2 binds Met-tRNAi to form the ternary complex, which then associates with the 40S ribosomal subunit together with other initiation factors such as eIF1, eIF1A, eIF3, and the eIF4F cap-binding complex. This assembly forms the 43S pre-initiation complex, which scans the mRNA for an AUG start codon and positions Met-tRNAi at the P site to begin translation.

Regulation of the eIF2-GTP-Met-tRNAi complex is a key control point for protein synthesis. Phosphorylation of the eIF2α subunit by stress-activated kinases (PERK, PKR, GCN2, and HRI) converts eIF2 into an inhibitor of its guanine nucleotide exchange factor eIF2B. This leads to reduced formation of ternary complexes and a global downregulation of translation, while enabling selective translation of certain mRNAs, such as ATF4, that help cells respond to stress.

Mechanistically, eIF2 cycles between GDP- and GTP-bound forms with the help of eIF2B. GTP hydrolysis during start codon recognition contributes to the release of Met-tRNAi to the ribosome and the recycling of eIF2-GDP back to eIF2-GTP via eIF2B. The ternary complex is conserved across eukaryotes and is essential for efficient and accurate initiation of protein synthesis.

Dysregulation of eIF2 signaling is implicated in various conditions, including neurodegenerative diseases, cancer, and viral infections. Because of its central role, the eIF2-GTP-Met-tRNAi pathway is a focus of research into translational control and potential therapeutic strategies.