EIF4E

eIF4E, or eukaryotic translation initiation factor 4E, is a cap-binding protein that recognizes the 5' cap structure of most eukaryotic mRNAs. It is the cap-binding subunit of the eIF4F complex, which also includes the RNA helicase eIF4A and the scaffolding protein eIF4G, and it is essential for cap-dependent translation initiation.

In the cytoplasm, eIF4E binds the 7-methylguanosine cap (m7G) at the 5' end of mRNAs and recruits eIF4G and eIF4A to form the eIF4F complex. This assembly helps to recruit the 40S ribosomal subunit and other initiation factors to the mRNA, facilitating scanning for the start codon and subsequent translation initiation.

Regulation of eIF4E activity is tightly controlled by 4E-binding proteins (4E-BPs), which compete with eIF4G for binding to eIF4E. When hypophosphorylated, 4E-BPs sequester eIF4E and repress translation; signaling through the mTOR pathway leads to phosphorylation of 4E-BPs, releasing eIF4E and allowing eIF4F formation and increased translation. eIF4E function can also be modulated by phosphorylation and by interactions with other regulatory proteins. Overexpression or amplification of EIF4E is observed in several cancers and is associated with enhanced translation of growth-promoting mRNAs.

eIF4E contains a cap-binding pocket formed by conserved aromatic residues, including tryptophans, that stack with the m7G cap. This surface also mediates interactions with eIF4G and 4E-BPs, governing assembly or disruption of the initiation complex. In addition to its cytoplasmic role, eIF4E has been implicated in nuclear processes such as mRNA export for a subset of transcripts. Therapeutically, disrupting eIF4E–eIF4G interactions or reducing eIF4E availability is explored as an anti-cancer strategy, with compounds like 4EGI-1 studied to inhibit eIF4F formation. Humans express EIF4E and related family members, including EIF4E2 (4E-HP), which can modulate cap-dependent translation in various contexts.