eIF4G

Eukaryotic initiation factor 4G (eIF4G) is a scaffold subunit of the eIF4F complex that mediates cap-dependent translation initiation in eukaryotic cells. In mammals, two main cytoplasmic variants exist: eIF4GI and eIF4GII, encoded by EIF4G1 and EIF4G2. In yeast, functional homologs include Tif4631 and Tif4632. eIF4G is part of the larger eIF4F complex that also includes eIF4E, the cap-binding protein, and the RNA helicase eIF4A.

Functionally, eIF4G serves as a platform that simultaneously binds eIF4E, eIF4A, the 40S ribosomal subunit via eIF3, and the poly(A)-binding protein (PABP) through its PABC domain. This network promotes recruitment of the ribosome to capped mRNAs and, by linking the 5' cap to the 3' poly(A) tail, supports mRNA circularization and efficient scanning for the start codon. eIF4G's activity is regulated by cellular signaling pathways, notably mTOR, which controls the availability of eIF4E via 4E-BP proteins. Viral proteases can also target eIF4G to reprogram translation during infection. The protein contains modular domains, including MIF4G and MA3 domains and HEAT repeats, which mediate interactions with its partners.

Role and evolution, and regulation: The modular architecture allows specialization among isoforms; differences in N- or C-terminal regions modulate interactions with cofactors and regulatory proteins. Beyond initiation, eIF4G participates in cellular stress responses where cap-dependent translation is selectively repressed. In some contexts, alternative translation initiation can occur via internal ribosome entry sites when eIF4G function is compromised. Dysregulation of eIF4F components has been linked to disease contexts, including cancer, where enhanced cap-dependent translation supports malignant growth.