eIF4GI

eIF4GI, or eukaryotic translation initiation factor 4G I, is a large cytoplasmic scaffolding protein that plays a central role in cap-dependent translation initiation in eukaryotic cells. It is a core component of the eIF4F complex, together with the cap-binding protein eIF4E and the RNA helicase eIF4A, and it also connects to the poly(A)-binding protein (PABP), promoting mRNA circularization and efficient ribosome recruitment to the 5' end of capped mRNAs.

The protein contains several modular domains that support its function. An N-terminal region binds eIF4E, linking eIF4GI to the 5' cap structure. A central MIF4G domain engages eIF4A and eIF3, helping to assemble the initiation machinery on the mRNA. The C-terminal region, rich in HEAT repeats and containing PAM2 motifs, interacts with PABP. As a scaffold, eIF4GI coordinates the recruitment of the 40S ribosomal subunit and initiation factors to the mRNA and facilitates scanning for the start codon.

Regulation of eIF4GI activity is tightly integrated with cellular signaling. The availability of eIF4E for eIF4G binding is controlled by 4E-BP1, which, when hypophosphorylated, sequesters eIF4E and inhibits cap-dependent translation. Nutrient and growth signals activate mTORC1, promoting 4E-BP1 phosphorylation and eIF4F assembly. Viral infection can disrupt eIF4GI function through proteolytic cleavage, shifting translation toward viral IRES-driven messages.

Isoforms and genes: in humans, EIF4G1 encodes eIF4GI and EIF4G2 encodes eIF4GII, a related protein. eIF4GI is typically the predominant form in many tissues and can, under some conditions, be complemented by eIF4GII. Dysregulation of cap-dependent translation involving eIF4GI-associated pathways is linked to various diseases, including cancer.