Regulation of Initiation Factor Activity

Abstract

The sequence of events in the initiation of protein synthesis in eukaryotes has been depicted for a number of years as shown in Fig. 1 (Thomas et al. 1981). The initiator Met-tRNA forms a ternary complex with eukaryotic initiation factor eIF-2 and GTP and binds subsequently to a 40S ribosomal subunit that arises by dissociation of a 80S ribosome in which process two factors, eIF-3 and eIF-4C play a role. The 40S preinitiation complex then attaches to messenger RNA which is mediated by four factors, eIF-4A, eIF-4B, eIF-4E, and eIF-1, ATP hydrolysis being a prerequisite. It has been postulated that the leader sequence of the messenger has to adopt a relaxed structure by melting of the secondary structures before the scanning by the 40S ribosome can take place (Kozak 1978; Grifo et al. 1982; Lee et al. 1983). When the initiation codon AUG is reached, the joining with the 60S occurs, triggering the release of the factors and ensuring that they can be used in a following round of initiation. However, recent studies in several laboratories indicated that another cycle, the eIF-2 cycle, has to be added to this scheme in order to complete the sequence of events in initiation (Amesz et al. 1979; Konieczny and Safer 1983; Siekierka et al. 1981; Panniers and Henshaw 1983; Clemens et al. 1982; Voorma et al. 1983; Safer 1983; Ochoa 1983). Reason for this additional cycle is the fact that eIF-2 is not released as free eIF-2, but as an eIF-2. GDP complex. Since the binding constant of GDP is at least one order of magnitude lower than for GTP, an exchange reaction has been postulated (Konieczny and Safer 1983; Siekierka et al. 1981; Panniers and Henshaw 1983; Clemens et al. 1982).