Initiation of protein synthesis in eukaryotes is a complex process requiring more than 12 different initiation factors, comprising over 30 polypeptide chains. The functions of many of these factors have been established in great detail; however, the precise role of some of them and their mechanism of action is still not well understood. Eukaryotic initiation factor 2A (eIF2A) is a single chain 65 kDa protein that was initially believed to serve as the functional homologue of prokaryotic IF2, since eIF2A and IF2 catalyze biochemically similar reactions, i.e., they stimulate initiator Met-tRNAi binding to the small ribosomal subunit. However, subsequent identification of a heterotrimeric 126 kDa factor, eIF2 (α,β,γ) showed that this factor, and not eIF2A, was primarily responsible for the binding of Met-tRNAi to 40S subunit in eukaryotes. It was found however, that eIF2A can promote recruitment of Met-tRNAi to 40S/mRNA complexes under conditions of inhibition of eIF2 activity (eIF2α-phosphorylation), or its absence. eIF2A does not function in major steps in the initiation process, but is suggested to act at some minor/alternative initiation events such as re-initiation, internal initiation, or non-AUG initiation, important for translational control of specific mRNAs. This review summarizes our current understanding of the eIF2A structure and function.
Keywords: alternative initiation; eIF2A; non-AUG initiation; stress response; translational initiation.
Conflict of interest statement
The authors declare no conflict of interest.
eIF2A, an initiator tRNA carrier refractory to eIF2α kinases, functions synergistically with eIF5B.Cell Mol Life Sci. 2018 Dec;75(23):4287-4300. doi: 10.1007/s00018-018-2870-4. Epub 2018 Jul 17. Cell Mol Life Sci. 2018. PMID: 30019215 Free PMC article.
The eIF2A knockout mouse.Cell Cycle. 2016 Nov 16;15(22):3115-3120. doi: 10.1080/15384101.2016.1237324. Epub 2016 Sep 29. Cell Cycle. 2016. PMID: 27686860 Free PMC article.
An mRNA-specific tRNAi carrier eIF2A plays a pivotal role in cell proliferation under stress conditions: stress-resistant translation of c-Src mRNA is mediated by eIF2A.Nucleic Acids Res. 2017 Jan 9;45(1):296-310. doi: 10.1093/nar/gkw1117. Epub 2016 Nov 28. Nucleic Acids Res. 2017. PMID: 27899592 Free PMC article.
Eukaryotic initiation factor eIF2.Int J Biochem Cell Biol. 1999 Jan;31(1):25-9. doi: 10.1016/s1357-2725(98)00128-9. Int J Biochem Cell Biol. 1999. PMID: 10216940 Review.
Structural Insights into the Mechanism of Scanning and Start Codon Recognition in Eukaryotic Translation Initiation.Trends Biochem Sci. 2017 Aug;42(8):589-611. doi: 10.1016/j.tibs.2017.03.004. Epub 2017 Apr 22. Trends Biochem Sci. 2017. PMID: 28442192 Review.