Roles of Co-eIF-2A and Co-eIF-2C in mammalian peptide chain initiation

Peptide chain initiation in animal cells begins with the formation of a ternary complex involving (eukaryotic initiation factor-2) eIF-2, GTP and the initiator methionyl t-RNA, Met-tRNA$\sb{\rm f}$. The next step is the transfer of Met-tRNA$\sb{\rm f}$ to the 40S ribosomal subunits in presence of mRNA to form the quaternary complex. Finally, the 60S ribosomal subunit joins in forming the 80S complex which is competent to initiate the protein biosynthesis. There is now ample evidence that in animal cells the control of peptide chain initiation is regulated by ancillary protein factors for ternary and 40S dependent quaternary complex formation. Co-eIF-2A and Co-eIF-2C are two such ancillary protein factors possessing activities to regulate the ternary and quartenary complex formation. Co-eIF-2A is a 94 kDa homogeneous protein which stimulates the ternary complex formation and protects it from degradation in presence of natural messages. Co-eIF-2C is a high molecular weight protein complex (605 kDa) consisting of eight different polypeptides. This protein also stimulates ternary complex formation in the presence of Mg$\sp{2+}$ and possesses some guanine nucleotide exchange factor (GEF) activity. Co-eIF-2C alone is sufficient in promoting AUG (a synthetic trinucleotide message) dependent quartenary complex formation. However, in the presence of natural messages both factors, namely, Co-eIF-2A and Co-eIF-2C are required to form such a complex. Our present understanding of the mechanism of peptide chain initiation is not complete. Different views exist as to the involvement of protein factors and individual polypeptides in ternary and subsequent quaternary complex formation. It has been demonstrated that a 180 kDa polypeptide (p180) is extremely important in protein synthesis initiation in animal cells. A precise role of p180 in ternary complex formation has been proposed. The controversy of Mg$\sp{2+}$ insensitivity of eIF-2 has also been resolved. Mg$\sp{2+}$-insensitive eIF-2 activity as reported by several laboratories might have been the result of the use of unusually high concentrations of Met-tRNA$\sb{\rm f}$ since the excess nucleotides chelates out the Mg$\sp{2+}$. Based on these observations, a new model for eukaryotic peptide chain initiation has been proposed