EIF4G

eIF4G (eukaryotic translation initiation factor 4 gamma) is a protein involved in bringing mRNA to the ribosome for translation, generally based on mRNA's distinctive guanosine cap. Species versions of eIF4G have been studied in everything from humans, to yeast, to wheat. However, eIF4G is exclusively found in domain Eukarya, not in domains Bacteria or Archaea (these do not have capped mRNA). As such be aware that when eIF4G is spoken of in this article, the statements will apply to many variants but not may not hold for all, and when comparing amongst species comparisons are relative to human eIF4G 1.

In all species eIF4G strongly associates with the protein that directly binds the mRNA cap: eIF4E. These two together are known as the complex eIF4F (generally also in association with the mRNA unwinding protein eIF4A).

Within the cell eIF4G is found primarily in the cytoplasm, usually bound to eIF4E; however, it's also found in the nucleus where it's function is unknown. Though in the nucleus it has been found to associate with the splicing complex it doesn't appear to be involved directly in RNA splicing. It also appears to have a role in nonsense mediated decay.

History
eIF4G stands for eukaryotic initiation factor 4 gamma (typically gamma is now replaced by G in the literature). Named so because it was initially isolated by fractionation (collecting small portions of fluid that had been separated on a column), it happened to be contained in fraction 4 gamma, and was involved in eukaryotic translation initiation.

eIF4G Binding Partners
eIF4G has been found to associate with a myriad of other proteins: eIF4E, MNK-1, eIF4A, CBP80, CBP20, PABP, and eIF3. eIF4G also directly binds mRNA and has multiple positively charged regions for this function (note: RNA is negatively charged, so RNA binding regions are usually very positively charged). Various IRES's also bind eIF4G directly, as do BTE CITE's.

Some RNA's that do not have caps (such as those containing IRES's) bind eIF4G specifically (in preference to other RNA binding proteins).

eIF4G in Translation Initiation
eIF4G essentially serves the function of bringing mRNA to the 40S ribosome.

There are essentially 3 ways that the 40S ribosome can come to recognize the start codon: scanning, internal entry, and shunting. Scanning is where the 40S ribosome slides along the RNA until recognizing a start site (typically an AUG sequence in "good context"). Internal entry is where the 40S ribosome doesn't start from the beginning (5' end) of the mRNA but instead starts from somewhere in the middle. Shunting is where after the 40S ribosome starts sliding along the mRNA it "jumps" or skips large sections, the mechanism for this is still unclear. eIF4G is required for all these types of intiation (with the exception of internal initiation by HCV or Cripavirus IRES initiation).

eIF4G in Disease
eIF4G has been implicated in breast cancer. It appears in increased levels in certain types of breast cancer (and others) and increases IRES containing mRNA production; these mRNAs produce hypoxia and stress related proteins that encourage blood vessel invasion (which is important for cancer cells—requiring large amounts of nutrients to divide quickly and form sizable tumors).

Importance in Virology
As previously mentioned eIF4G is bound by IRES's which were initially discovered in viruses. Viral some IRES's directly bind eIF4G, and co-opt it for gaining access to the ribosome. Some cellular RNA's also contain IRES's (including eIF4G itself).

Some viruses do this by cutting off part of eIF4G such that eIF4E no longer binds it. This has the effect of preventing most cellular mRNA's from binding eIF4G (which require eIF4E to ride along on eIF4G); however, the few cellular mRNAs with IRES's still translate under these conditions.

Binding sites for viral IRES's: EMCV IRES aa 746-949.