Eukaryotic initiation factor 4F (eIF4F) is a heterotrimericprotein complex that binds the5' cap ofmessenger RNAs (mRNAs) to promoteeukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: theDEAD-boxRNA helicaseeIF4A, the cap-binding proteineIF4E, and the large "scaffold" proteineIF4G.[2][3] The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since.[3]
eIF4F is important for recruiting thesmall ribosomal subunit (40S) to the5' cap of mRNAs duringcap-dependent translation initiation. Components of the complex are also involved incap-independent translation initiation; for instance, certain viralproteases cleave eIF4G to remove the eIF4E-binding region, thus inhibiting cap-dependent translation.[3]
Structures of eIF4F components have been solved individually and as partial complexes by a variety of methods, but no complete structure of eIF4F is currently available.[4]
In mammals, the eIF4E•G•A trimeric complex can be directly purified from cells, while only the two subunit eIF4E•G can be purified from yeast cells. This suggests that the interaction between the eIF4A and eIF4G in yeast is not as stable.[3]eIF4E binds them7G5' cap and the eIF4G scaffold, connecting the mRNA 5' terminus to a hub of otherinitiation factors and mRNA. The interaction of eIF4G•A is thought to guide the formation of a single-stranded RNA landing pad for the43S preinitiation complex (43S PIC) via eIF4A'sRNA helicase activity.[3]
The eIF4F proteins interact with a number of different binding partners, and there are multiple genetic isoforms ofeIF4A,eIF4E, andeIF4G in the human genome. In mammals, eIF4F is bridged to the 40S ribosomal subunit byeIF3 viaeIF4G, whilebudding yeast lacks this connection.[3] Interactions betweeneIF4G andPABP are thought to mediate the circularization of mRNA particles, forming a "closed-loop" thought to stimulate translation.[5]
| Subunit | MW (kDa)[A] | Isoforms | Key Features |
|---|---|---|---|
| eIF4A | 46 | eIF4A1,eIF4A2,eIF4A3 | DEAD-box RNA helicase. Binds mRNA, eIF4G,eIF4B,eIF4H, andPDCD4. Inhibited by the small moleculeshippuristanol,[6]rocaglamide A (RocA),[7] and pateamine A.[8] |
| eIF4E | 25 | eIF4E1,eIF4E2,eIF4E3 | Cap-binding protein. Binds eIF4G,4EBP1,4EBP2 and4EBP3. |
| eIF4G | 175 | eIF4G1,eIF4G3 | "Scaffold" protein. Binds mRNA, eIF4A, eIF4E, andPABP. |
A Approximate molecular weight for human proteins.
In addition to the major proteins encompassing the eIF4F trimer, the eIF4F complex functionally interacts with proteins includingeIF4B andeIF4H. The unusual isoform of eIF4G,eIF4G2 or DAP5, also appears to perform a non-canonical translation function.
TheeIF4E subunit of eIF4F is an important target ofmTOR signaling through theeIF4E binding protein (4E-BP).[3] Phosphorylation of 4E-BPs by mTOR prevents their binding to eIF4E, freeing eIF4E to bind eIF4G and participate in translation initiation.[3]
