Eukaryotic translation initiation factor 4E–Eukaryotic translation initiation factor 4 gamma 1 protein–protein interface (eIF4E–eIF4G1 interface)

The eIF4E–eIF4G1 protein–protein interface is a fundamental regulatory junction in the eukaryotic translation initiation process (UniProt P06730; UniProt Q04637). Eukaryotic translation initiation factor 4E (eIF4E) recognizes and binds the 5' cap structure of mRNA, while eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) acts as a large scaffolding protein that recruits other initiation factors and the 40S ribosomal subunit (PubMed: 17317181). This interaction is the rate-limiting step for cap-dependent translation, which is frequently hijacked in various malignancies to drive the synthesis of oncogenic proteins (PubMed: 25847970). Overexpression of eIF4E or the loss of its natural inhibitors, the 4E-binding proteins (4E-BPs), leads to increased eIF4E–eIF4G1 complex formation, promoting tumor growth, metastasis, and resistance to chemotherapy (PubMed: 21454756). Therapeutic strategies targeting this interface involve small molecules or peptidomimetics that competitively bind to the eIF4G-binding site on eIF4E. By disrupting this assembly, these inhibitors selectively reduce the translation of "weak" mRNAs with complex 5' leaders, such as those encoding c-Myc, Cyclin D1, and VEGF, while having a minimal effect on the translation of housekeeping genes. Consequently, targeting the eIF4E–eIF4G1 interface offers a potent mechanism to suppress the oncogenic proteome in cancer cells.

Other names

eIF4E-eIF4G interactioneIF4F complex assemblyeIF4E/eIF4G1 PPIeIF4E-eIF4G1 complex

Competitive inhibition of the eIF4E-eIF4G1 interaction to prevent eIF4F complex assembly and selectively inhibit the cap-dependent translation of oncogenic mRNAs.