Question

Cells that accumulate misfolded proteins initiate a stress response that includes reducing protein translation by inhibiting the initiation stage of translation. First explain the three stages of initiation of protein translation in eukaryotic cells. Next explain the mechanism by which translation is inhibited as part of the stress response.

The three stages are 43S preinitiation complex, 48S initiation complex, and 80S initiation complex but I don't know how to explain them and what happens during each stage.

Answer 1

in eukaryotic initiation process

1. Initiation factors (eIFs) binds to the 40S ribosomal subunit

eIF2-GTP binds to tRNA forming ternary complex

eIF3 then binds to the ternary complex and also the 40S subunit forming the 43S initiation complex.

2. eIF4Fcomplex (eIF4G, eIF4E,eIF4A) binds to mRNA .

eIF4G scaffold protein

eIF4E cap binding protein (binds to 5' cap)

eIF4A helicase enzyme

eIF4B binds to the eIF4F-mRNA complex which then joins the 43S complex. The 43S translocates along mRNA (scanning process) until it encounters AUG (initiation codon). Binding of 43S to initiation codon forms the 48S complex.

the poly A tail of the mRNA also interacts with eIF4G this maintains a circular RNA structure during translation.

3. as a final initiationstep, eIF5B helps in joining the 60S subunit to the complex forming an 80S initiation complex.

mechanism of inhibition of translation initiation under stress:

there are two mechanisms: 5'CAP recognition inhibition and Ternary complex formation inhibition.

under stress condition, eIF4E binding protein (eIF4EBP) which share a similar structure with eIF4G competes for 5' CAP binding. Binding of eIF4EBP to mRNA cap prevents translation initiation

ternary complex formation by eIF2 for initiation of translation is inhibited under stress condition by phosphorylation of eIF2 at the alpha subunit. This stops the eIF2 from getting activated (i.e it cannot bind to GTP).