PEK family, also called eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation stage of eukaryotic translation. These proteins help stabilize the formation of ribosome pre-start complexes around the start codon and are important inputs for post-transcriptional gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet, called the 43S pre-start complex (43S PIC). The other factors of the eIF4F complex (eIF4A, E and G) recruit 43S PIC to the five-factor cap structure of the mRNA, from which the 43S particles scan 5 '-> 3' along the mRNA to reach the AUG start codon. Met-tRNAiMet's recognition of the start codon promoted the release of gated phosphate and eIF1, thus forming a 48S pre-start complex (48S PIC), and subsequently recruited large number of 60S ribosomal subunits to form 80S ribosomes. There are more eukaryotic promoters than prokaryotic promoters, which reflects the greater biological complexity of eukaryotic translation.

eIF1 and eIF1A

Both eIF1 and eIF1A bind to the 40S ribosomal subunit-mRNA complex. Together, they induce the "open" conformation of mRNA-binding channels, which is essential for scanning, tRNA delivery, and initiation of codon recognition. In particular, the dissociation of eIF1 from the 40S subunit was thought to be a key step in initiation codon recognition. eIF1 and eIF1A are small proteins (13 and 16 kDa in humans, respectively) and are part of the 43S PIC. eIF1 binds near the ribosome P site, while eIF1A binds near the A site in a manner is similar with the structural and functional bacterial counterparts IF3 and IF1, respectively.

Figure 1. Protein structure of eIF1.

eIF3

eIF3 independently binds the 40S ribosomal subunit, multiple initiation factors, and cellular and viral mRNA.In mammals, eIF3 is the largest initiation factor, made up of 13 subunits (a-m). It has a molecular weight of ~800 kDa and controls the assembly of the 40S ribosomal subunit on mRNA that have a 5' cap or an IRES. eIF3 may use the eIF4F complex, or alternatively during internal initiation, an IRES, to position the mRNA strand near the exit site of the 40S ribosomal subunit, thus promoting the assembly of a functional pre-initiation complex. In many human cancers, eIF3 subunits are overexpressed (subunits a, b, c, h, i, and m) and underexpressed (subunits e and f). One potential mechanism to explain this disregulation comes from the finding that eIF3 binds a specific set of cell proliferation regulator mRNA transcripts and regulates their translation. eIF3 also mediates cellular signaling through S6K1 and mTOR/Raptor to effect translational regulation.

Figure 2. Protein structure of eIF2.

eIF4F

The eIF4F complex consists of three subunits: eIF4A, eIF4E, and eIF4G. Each subunit has multiple human isoforms, and there are other eIF4 proteins: eIF4B and eIF4H. eIF4G is a 175.5-kDa scaffold protein that interacts with the eIF4F complex with eIF3 and Poly (A) binding protein (PABP) and other members of the protein. eIF4E recognizes and binds to the 5 'cap structure of mRNA, while eIF4G binds to PABP, which binds to the poly (A) tail, which may circularize and activate the bound mRNA. eIF4A (a DEAD box RNA helicase) is important for solving the secondary structure of mRNA. eIF4B contains two RNA-binding domains-one non-specifically interacts with the mRNA, while the second specifically binds to the 18S portion of the small ribosome subunit. It acts as an anchor and key cofactor for eIF4A. It is also a substrate of S6K, and when phosphorylated, it promotes the formation of pre-starting complexes. In vertebrates, eIF4H is an additional initiation factor and functions similarly to eIF4B.

Figure 3. Protein structure of eIF4.

eIF5

eIF5 is a GTPase activating protein that helps large ribosomal subunits bind to small subunits. It is necessary for eIF2 to hydrolyze GTP and contains the unusual amino acid hysupsine. eIF5A is a eukaryotic homolog of EF-P. It helps in elongation and plays a role in termination. eIF5B is a GTPase involved in the assembly of intact ribosomes. It is a functional eukaryotic analog of bacterial IF2.

Figure 4. Protein structure of eIF5.

Disease

Of the known eukaryotic initiation factors, eIF2B is most closely related to human genetic diseases. Autosomal hereditary recessive mutations in the five subunit genes of eIF2B can cause white matter abnormalities, which are clinically manifested as a series of severe continuous symptoms, called "eIF2B-related disorders." Typical examples are white matter disease, ie vanishing white matter (VWM) and ovarian failure. This disorder is long-lasting, worsening with age, and can worsen and cause death when infected with fever or minor brain trauma. At its worst, it can cause death in infancy, and if it persists to the end it can cause adult ovarian development to fail and may be accompanied by neurodegeneration.

Reference

1. Jackson RJ; et al. The mechanism of eukaryotic translation initiation and principles of its regulation. Nature Reviews. Molecular Cell Biology. 2010, 11 (2): 113-27.