Eukaryotic initiation factor

Eukaryotic initiation factors (eIF) are proteins involved in the initiation phase of eukaryotic translation. They function in forming a complex with the 40S ribosomal subunit and Met-tRNAi called the 43S preinitation complex (PIC), recognizing the 5' cap structure of mRNA and recruiting the 43S PIC to mRNA, promoting ribosomal scanning of mRNA and regulating recognition of the AUG initiation codon, and joining of the 60S ribosomal subunit to create the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors due to greater biological complexity of eukaryotic cells.

The protein RLI is known to have an essential, probably catalytic role in the formation of initiation complexes as well.

eIF4 (eIF4F)
The eIF4 initiation factors include eIF4A, eIF4B, eIF4E, and eIF4G. eIF4F is often used to refer to the complex of eIF4A, eIF4E, and eIF4G.

eIF4G is a scaffolding protein that interacts with eIF3 (see below), as well as the other members of the eIF4F complex. eIF4E recognizes and binds to the 5' cap structure of mRNA, while eIF4G binds to Poly(A)-binding protein which binds the poly(A) tail, circularizing and activating the bound mRNA.

eIF4A– a DEAD box RNA helicase– is important for resolving mRNA secondary structures. eIF4B contains two RNA-binding domains– one non-specifically interacts with mRNA, whereas the second specifically binds the 18S portion of the small ribosomal subunit. It acts as an anchor, as well as a critical co-factor for eIF4A. It is a substrate of S6K, and, when phosphorylated, it promotes the formation of the pre-initiation complex. In vertebrates, eIF4H is an additional initiation factor with similar function to eIF4B.

eIF1 & eIF3
eIF1, eIF1A, and eIF3, all bind to the ribosome subunit-mRNA complex. They have been implicated in preventing the large ribosomal subunit from binding the small subunit before it is ready to commence elongation.

In mammals, eIF3 is the largest scaffolding initiation factor, made up of 13 subunits (a-m). It is roughly ~750 kDa and it controls the assembly of 40S ribosomal subunit on mRNA that have a 5' cap or an IRES. eIF3 uses the eIF4F complex or IRES (Internal Ribosomal Entry Site) from viruses to position the mRNA strand near the exit site of the 40S ribosome subunit, thus promoting the assembly of the pre-initiation complex.

In many cancers, eIF3 is overexpressed. Under serum-deprived conditions (inactive state), eIF3 is bound to S6K1. On stimulation either by mitogens, growth factors, or drugs, mTOR/Raptor complex gets activated and, in turn, binds and phosphorylates S6K1 on T389 (linker region), causing a conformational change that causes the kinase S6K1 to dissociate from eIF3. The T389 phosphorylated S6k1 is then further phosphorylated by PDK1 on T229. This second phosphorylation fully activates the S6K1 kinase, which can then phosphorylate eIF4B, S6 and other protein targets.

eIF2

 * See main article at EIF-2

eIF2 is a GTP-binding protein responsible for bringing the initiator tRNA to the P-site of the pre-initiation complex. It has specificity for the methionine-charged initiator tRNA, which is distinct from other methionine-charged tRNAs specific for elongation of the polypeptide chain. Once it has placed the initiator tRNA on the AUG start codon in the P-site, it hydrolyzes GTP into GDP, and dissociates. This hydrolysis, also signals for the dissociation of eIF3, eIF1, and eIF1A, and allows the large subunit to bind. This signals the beginning of elongation.

eIF2 has three subunits, eIF2-α, β, and γ. The former is of particular importance for cells that may need to turn off protein synthesis globally. When phosphorylated, it sequesters eIF2B (not to be confused with beta), a GEF. Without this GEF, GDP cannot be exchanged for GTP, and translation is repressed.

eIF2α-induced translation repression occurs in reticulocytes when starved for iron. In addition, protein kinase R (PKR) phosphorylates eIF2α when dsRNA is detected in many multicellular organisms, leading to cell death.

eIF5 & eIF5B
eIF5A is a GTPase-activating protein, which helps the large ribosomal subunit associate with the small subunit. It is required for GTP-hydrolysis by eIF2 and contains the unusual amino acid hypusine.

eIF5B is a GTPase, and is involved in assembly of the full ribosome (which requires GTP hydrolysis).

eIF6
eIF6 performs the same inhibition of ribosome assembly as eIF3, but binds with the large subunit.