Fig 4. A model for the molecular interactions likely to account for the effect of BZW1 and BZW2 on stringency of start codon selection.
During scanning, when the 40S subunit is in the open conformation, eIF1 is bound near the P-site and monitors the interaction between tRNAiMet and nucleotide triplets in the mRNA. The eIF5 C-terminal domain is loosely bound to eIF1 working as a lid to prevent the premature release of eIF1 from the PIC. (A) Under low BZW levels, the eIF2β N-terminal domain and eIF5 C-terminal domain occasionally interact pulling eIF5 away from eIF1, allowing its looser association with the PIC. The lower affinity of eIF1 for the PIC facilitates more frequent initiation at near-cognate or suboptimal AUG codons. (B) BZW, perhaps through its C-terminal HEAT domain, binds to the eIF2β N-terminal domain. When levels of BZW protein are high this interaction is favored, and this prevents interaction between eIF2β and eIF5. This leaves the “lid” on eIF1 closed, essentially increasing its effective concentration on the PIC and this enhances stringency of start codon selection, resulting in lower frequency of initiation at near-cognate start codons or poor context AUG triplets, including the start codons of BZW genes, with ribosome continuing to scan in the 3’ direction for a better start codon.