An eIF5/eIF2 complex antagonizes guanine nucleotide exchange by eIF2B during translation initiation

In eukaryotic translation initiation, the eIF2·GTP/Met‐tRNAiMet ternary complex (TC) binds the eIF3/eIF1/eIF5 complex to form the multifactor complex (MFC), whereas eIF2·GDP binds the pentameric factor eIF2B for guanine nucleotide exchange. eIF5 and the eIF2Bε catalytic subunit possess a conserved eIF2‐binding site. Nearly half of cellular eIF2 forms a complex with eIF5 lacking Met‐tRNAiMet, and here we investigate its physiological significance. eIF5 overexpression increases the abundance of both eIF2/eIF5 and TC/eIF5 complexes, thereby impeding eIF2B reaction and MFC formation, respectively. eIF2Bε mutations, but not other eIF2B mutations, enhance the ability of overexpressed eIF5 to compete for eIF2, indicating that interaction of eIF2Bε with eIF2 normally disrupts eIF2/eIF5 interaction. Overexpression of the catalytic eIF2Bε segment similarly exacerbates eIF5 mutant phenotypes, supporting the ability of eIF2Bε to compete with MFC. Moreover, we show that eIF5 overexpression does not generate aberrant MFC lacking tRNAiMet, suggesting that tRNAiMet is a vital component promoting MFC assembly. We propose that the eIF2/eIF5 complex represents a cytoplasmic reservoir for eIF2 that antagonizes eIF2B‐promoted guanine nucleotide exchange, enabling coordinated regulation of translation initiation.

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