EIF4F

eIF4F is a eukaryotic initiation factor complex that mediates the recruitment of ribosomes to capped mRNA during the initiation phase of cap-dependent translation. The complex consists of three core subunits: eIF4E, the cap-binding protein; eIF4A, an RNA helicase; and eIF4G, a large scaffolding protein that coordinates interactions with other initiation factors and with the poly(A) binding protein (PABP).

Mechanism: eIF4E recognizes and binds the 5' m7G cap of mRNA. eIF4A uses ATP to unwind secondary structures in the 5' untranslated region, enabling scanning by the 40S ribosomal subunit. eIF4G binds eIF4E and eIF3, linking the mRNA cap to the ribosome and, via interactions with PABP, promoting mRNA circularization that enhances translation efficiency.

Regulation: Formation and activity of eIF4F are tightly controlled. In many cells, 4E-BP proteins bind eIF4E and prevent eIF4F assembly; phosphorylation of 4E-BP by the mTOR pathway releases eIF4E, allowing eIF4F assembly. eIF4G contains binding sites for eIF3, eIF4A, and PABP, integrating cap recognition, helicase activity, and ribosome recruitment.

Clinical and biological relevance: Dysregulation of the eIF4F axis, including eIF4E overexpression or 4E-BP suppression, is associated with increased translation and oncogenesis in various cancers. Viral infection and cellular stress conditions can also modulate eIF4F activity to control translation.