The rate-limiting step in translation is initiation and this level therefore serves as the site for translation control. Due to the presence of many steps within the translation initiation process, there are subsequently numerous opportunities also for regulation of this system. A great deal of control is achieved by strong versus weak contexts surrounding AUG start codons, but a great majority of control is also mediated through the phosphorylation of initiation factors. Phosphorylation of initiation factors can lead to either inhibitory or stimulatory effects. In addition, control can also be mediated through the blocking of coding regions due to the presence of protein binding and 5' UTR regulatory elements (Weaver, 1999).
An example of phosphorylation regulation can be seen in reticulocytes which make hemoglobin. Regulation of their production is at the level of translation initiation. The absence of heme allows the activity of a protein kinase called the heme-controlled repressor HCR to phosphoarylate the eIF-2 subunit, eIF-2alpha, which now can bind more strongly to eIF-2B. This strong complexing interaction subsequently prevents eIF-2B from carrying out its functions, which is to exchange GTP for GDP on eIF-2, thereby inactivating eIF-2. With no GTP exchange, eIF-2 cannot attach initiator tRNA to the 40S ribosomes, thereby halting translation initiation. Interferons, which are anti-viral proteins, also follow a similar pathway to prevent cell growth during a viral infection (Rhoads 1993).
By targeting sequences or initiation factors, translation initiation is capable of being controlled through simple mechanisms, such as phosphorylating initiation factors which are critical for initiation. The critical requirement of initiation factors, attributed through their functional domains, can be further understood by looking at their evolutionary progression.