EIF4G
Encyclopedia
eIF4G 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
.
Some RNA's that do not have caps (such as those containing IRES's) bind eIF4G specifically (in preference to other RNA binding proteins).
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).
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.
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
for translation, generally based on mRNA's distinctive guanosine cap
5' cap
The 5' cap is a specially altered nucleotide on the 5' end of precursor messenger RNA and some other primary RNA transcripts as found in eukaryotes. The process of 5' capping is vital to creating mature messenger RNA, which is then able to undergo translation...
. Species versions of eIF4G have been studied in everything from humans, to yeast
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
, to wheat
Wheat
Wheat is a cereal grain, originally from the Levant region of the Near East, but now cultivated worldwide. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...
. However, eIF4G is exclusively found in domain
Domain (biology)
In biological taxonomy, a domain is the highest taxonomic rank of organisms, higher than a kingdom. According to the three-domain system of Carl Woese, introduced in 1990, the Tree of Life consists of three domains: Archaea, Bacteria and Eukarya...
Eukarya, not in domains Bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
or Archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
(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
Eukaryotic translation initiation factor 4 gamma
Eukaryotic translation initiation factor 4 gamma 1 is a protein that in humans is encoded by the EIF4G1 gene.-Interactions:Eukaryotic translation initiation factor 4 gamma has been shown to interact with MKNK1, EIF4A1, EIF4E, MKNK2 and PABPC1....
.
In all species eIF4G strongly associates with the protein that directly binds the mRNA cap: eIF4E
EIF4E
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein which in humans is encoded by the eIF4E gene.- Function :...
. These two together are known as the complex eIF4F (generally also in association with the mRNA unwinding
Helicase
Helicases are a class of enzymes vital to all living organisms. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands using energy derived from ATP hydrolysis.-Function:Many cellular processes Helicases are a...
protein eIF4A
Eif4a
The eukaryotic initiation factor-4A family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits...
).
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
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
. It also appears to have a role in nonsense mediated decay
Nonsense mediated decay
Nonsense-mediated decay is a cellular mechanism of mRNA surveillance that functions to detect nonsense mutations and prevent the expression of truncated or erroneous proteins. Following transcription, precursor mRNA undergoes an assemblage of ribonucleoprotein components followed by regulatory...
.
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
Hepatitis C virus
Hepatitis C virus is a small , enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae...
or Cripavirus
Cripavirus
Cripaviruses are a genus of + sense, single-stranded RNA viruses. If a ssRNA virus is +sense, it means that the viruses can produce proteins directly from their RNA genome upon entering a cell; and therefore, may not require an RNA polymerase packaged in with it, as this may be produced from the...
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.