eIF2 Initiation Factor

eIF2 is multi-functional protein, which is the site of many regulatory processes of initiation. eIF2 accomplishes many of its functions by being a heterometric protein, consisting of three functional subunits, alpha, beta, and gamma. eIF2, along with GTP and aminoacylated initiator methionyl-tRNA, bind the 40S ribosomal subunit, creating the 43S complex, which is now capable of binding mRNA. eIF2 is released with GDP attached, after eIF5 triggers the hydrolysis of GTP. REgeneration of eIF2 further requires eIF2A to catalyze the exchange of GDP on eIF2, for GTP, thereby allowing a second round of 43S formation on mRNA (Pestova et al., 2000).

Functions of eIF2 can be allocated to its composition into three subunits. Alterations of residual composition of the alpha subunit, confer ribosomes the ability to begin translation without the presence of an AUG inititiation codon (Cigan et al., 1989), depicting eIF2 as playing a role in ribosomal recognition of the initiation codon. The beta subunit varies between different species, with the exception of two motifs, a C-termianl C2-C2 zinc finger-like domain and N-terminal polylysine tracts. Mutations within or adjacent to the zinc finger-like motif, allow initiation to begin at a UUG codon when AUG is missing (Donahue et al., 1988; Castilho et al., 1992), implying a role in start site selection. The polylysine tracts are required for the binding of mRNA, but not tRNA, providing the betw subunit with its strong ability to bind mRNA (Flynn et al., 1994). The functions of the gamma subunit, which are to bind GTP and Met-tRNAi, were discovered through photoaffinity labeling of eIF2 complexed with GTP analogues and linking of eIF2 to tRNA (Erickson et al., 1996). eIF2 gamma subunit displays strong homology with prokaryotic elongation factor EF-Tu. Like eIF2 gamma, EF-Tu binds aminoacylated tRNA in a GTP-dependent mechanism and may prove effective as a prototype for eIF2 gamma GTP-binding of initiation tRNA. Mutations within the guanine ring-binding loop in eIF2 gamma, increased initiation at other codons rather than the AUG codon (Dorris et al., 1996). All three subuni of eIF2 are therefore believed to select the start site of initiation (Pestove and Hellen 2000).