Eukaryotic translation initiation factor 4E:Eukaryotic translation initiation factor 4 gamma protein-protein interaction (eIF4E:eIF4G PPI)

The eIF4E:eIF4G protein-protein interaction is a fundamental regulatory node in eukaryotic translation initiation, serving as the rate-limiting step for cap-dependent protein synthesis (Sonenberg & Hinnebusch, 2009). eIF4E (Eukaryotic translation initiation factor 4E) is the cap-binding protein that recognizes the 5' methyl-guanosine cap of mRNA, while eIF4G (Eukaryotic translation initiation factor 4 gamma) acts as a large scaffolding protein that recruits the RNA helicase eIF4A and the 40S ribosomal subunit to form the eIF4F complex (Gingras et al., 1999). This interaction is naturally regulated by 4E-binding proteins (4E-BPs), which compete with eIF4G for a conserved binding site on eIF4E; phosphorylation of 4E-BPs by the mTOR pathway releases eIF4E to allow translation (Pause et al., 1994). In many human cancers, eIF4E is overexpressed or hyperactivated, leading to the preferential translation of "weak" mRNAs that encode pro-survival and pro-growth proteins such as c-Myc, Cyclin D1, and Bcl-2, thereby promoting tumorigenesis and metastasis (Malka-Mahieu et al., 2017). Pharmacological disruption of the eIF4E:eIF4G interaction using small molecules like 4EGI-1 or 4E1RCat mimics the action of 4E-BPs, effectively suppressing the translation of oncogenic proteins and inducing apoptosis in transformed cells (Moerke et al., 2007; Cencic et al., 2011). Beyond oncology, this interaction is a target for antiviral therapies, as many viruses, including coronaviruses, hijack the host's eIF4F complex to facilitate the translation of viral proteins (Cencic et al., 2011).

Other names

eIF4E-eIF4G interactioneIF4E/eIF4G complex assemblyeIF4F complex formationeIF4E-eIF4G bindingCap-binding protein:scaffold protein interaction

Inhibition of the protein-protein interaction between the cap-binding protein eIF4E and the scaffolding protein eIF4G, which prevents the assembly of the eIF4F translation initiation complex and selectively suppresses the translation of oncogenic mRNAs.