Figure 2. The PIC Associated with mRNA Binding, Scanning, and AUG Recognition.

(A) A hypothetical model showing (I) the 48S PIC in an open, scanning-conducive conformation with a non-AUG codon in the P-site and eIF1A in the A-site. GTP in the ternary complex is partially hydrolyzed in a manner stimulated by eIF5, but Pi release from eIF2-GDP-Pi is blocked by eIF1, bound near the P-site. Both eIF1 and eIF1A promote scanning. (II) Pairing of Met-tRNA_i ^Met with the AUG codon elicits a conformational change that increases the separation between the eIF1A C-terminal tail (CTT) and eIF1 and results in tighter binding of eIF1A to the PIC, mediated by the eIF1A N-terminal tail (orange) and by neutralizing an antagonistic effect of the eIF1A CTT on PIC interaction (perhaps via CTT-eIF5 interaction). (III) Dissociation of eIF1 from its location near the P-site allows release of Pi from eIF2-GDP-Pi, an irreversible step that drives GTP hydrolysis to completion and finalizes start codon selection (adapted from Fekete et al., 2007).

(B) Cryo-EM reconstruction of a yeast 40S subunit alone (Apo) or bound to eIF1 and/or eIF1A (pt, platform; n, neck; *, connection between shoulder and head induced by eIF1/eIF1A binding). (Reprinted from Passmore et al., 2007.)

(C) Cryo-EM model of eukaryotic 40S subunit bound by the hepatitis C virus IRES (purple) and mammalian eIF3 (pink) (from Siridechadilok et al., 2005, Science 310, 1513–1515; reprinted with permission from AAAS).

(D) Model for the scanning PIC, based on new findings on the topology of the eIF4A/4G/4H helicase complex and spatial arrangement of its RNA-binding surfaces, which places eIF4A on the 3′ side of the PIC (reprinted from Marintchev et al., 2009).