Eukaryotic translation initiation is controlled by cooperativity effects within ternary complexes of 4E-BP1, eIF4E, and the mRNA 5′ cap

• A thermodynamic cycle for cooperativity during translation inhibition is proposed.
• Affinity of 4E-BP1 to eIF4E increases markedly upon binding to mRNA 5′ cap.
• 4E-BP1 flanking regions play some role in binding to eIF4E/cap but not to apo-eIF4E.
• 4E-BP1 stabilizes the eIF4E conformation capable of binding the cap.
• 4E-BP1 facilitates dissociation of eIF4E from the mRNA 5′ cap.

Initiation is the rate-limiting step during mRNA 5′ cap-dependent translation, and thus a target of a strict control in the eukaryotic cell. It is shown here by analytical ultracentrifugation and fluorescence spectroscopy that the affinity of the human translation inhibitor, eIF4E-binding protein (4E-BP1), to the translation initiation factor 4E is significantly higher when eIF4E is bound to the cap. The 4E-BP1 binding stabilizes the active eIF4E conformation and, on the other hand, can facilitate dissociation of eIF4E from the cap. These findings reveal the particular allosteric effects forming a thermodynamic cycle for the cooperative regulation of the translation initiation inhibition.

Structured summary of protein interactions4E-BP1 and eIF4Ebind by cosedimentation in solution (View interaction)