![EIF4E](https://upload.wikimedia.org/wikipedia/commons/8/8f/EIF4E.png)
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''EIF4E''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Structure and function
Most
eukaryotic
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
cellular
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
s are blocked at their 5'-ends with the 7-methyl-
guanosine
Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose ( ribofuranose) ring via a β-N9- glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate ...
five-prime cap
In molecular biology, the five-prime cap (5′ cap) is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation ...
structure, m7GpppX (where X is any nucleotide). This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. eIF4E is a
eukaryotic translation initiation factor involved in directing
ribosomes to the cap structure of mRNAs. It is a 24-kD poly
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
that exists as both a free form and as part of the
eIF4F
Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-b ...
pre-initiation complex.
Almost all cellular mRNA require eIF4E in order to be translated into protein. The eIF4E polypeptide is the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis.
The other subunits of eIF4F are a 47-kD polypeptide, termed
eIF4A
The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that ...
,
that possesses
ATPase and RNA
helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separatin ...
activities, and a 220-kD scaffolding polypeptide,
eIF4G
Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeas ...
.
Some viruses cut eIF4G in such a way that the eIF4E binding site is removed and the virus is able to translate its proteins without eIF4E. Also some cellular proteins, the most notable being heat shock proteins, do not require eIF4E in order to be translated. Both viruses and cellular proteins achieve this through an
internal ribosome entry site An internal ribosome entry site, abbreviated IRES, is an RNA element that allows for translation initiation in a cap-independent manner, as part of the greater process of protein synthesis. In eukaryotic translation, initiation typically occurs at ...
in the RNA.
Regulation
Since eIF4E is an initiation factor that is relatively low in abundance, eIF4E is a potential target for transcriptional control. Regulation of eIF4E may be achieved via three distinct mechanisms: transcription, phosphorylation, and inhibitory proteins.
a. Regulation of eIF4E by Gene Expression
The mechanisms responsible for eIF4E transcriptional regulation are not entirely understood. However, several reports suggest a correlation between myc levels and eIF4E mRNA levels during the cell cycle. The basis of this relationship was further established by the characterization of two myc-binding sites (CACGTG E box repeats) in the promoter region of the eIF4E gene. This sequence motif is shared with other in vivo targets for myc and mutations in the E box repeats of eIF4E inactivated the promoter region, thereby diminishing its expression.
b. Regulation of eIF4E by Phosphorylation
Stimuli such as hormones, growth factors, and mitogens that promote cell proliferation also enhance translation rates by phosphorylating eIF4E. Although eIF4E phosphorylation and translation rates are not always correlated, consistent patterns of eIF4E phosphorylation are observed throughout the cell cycle; wherein low phosphorylation is seen during G
0 and M phase and wherein high phosphorylation is seen during G
1 and S phase. This evidence is further supported by the crystal structure of eIF4E which suggests that phosphorylation on serine residue 209 may increase the affinity of eIF4E for capped mRNA.
c. Regulation of eIF4E by Inhibitory Proteins
Assembly of the eIF4F complex is inhibited by proteins known as eIF4E-binding proteins (4E-BPs), which are small heat-stable proteins that block cap-dependent translation.
Non-phosphorylated 4E-BPs interact strongly with eIF4E thereby preventing translation; whereas phosphorylated 4E-BPs bind weakly to eIF4E and thus do not interfere with the process of translation. Furthermore, binding of the 4E-BPs inhibits phosphorylation of Ser209 on eIF4E.
The Role of eIF4E in Cancer
The role of eIF4E in cancer was established after Lazaris-Karatzas et al. made the discovery that overexpressing eIF4E causes tumorigenic transformation of fibroblasts. Since this initial observation, numerous groups have recapitulated these results in different cell lines. As a result, eIF4E activity is implicated in several cancers including cancers of the breast, lung, and prostate. In fact, transcriptional profiling of metastatic human tumors has revealed a distinct metabolic signature wherein eIF4E is known to be consistently up-regulated.
FMRP represses translation through EIF4E binding
Fragile X mental retardation protein (
FMR1
''FMR1'' (Fragile X Messenger Ribonucleoprotein 1) is a human gene that codes for a protein called ''fragile X messenger ribonucleoprotein'', or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development ...
) acts to regulate translation of specific mRNAs through its binding of eIF4E. FMRP acts by binding
CYFIP1
Cytoplasmic FMR1-interacting protein 1 is a protein that in humans is encoded by the ''CYFIP1'' gene.
Interactions
CYFIP1 has been shown to interact with FMR1, to the exclusion of FXR1
Fragile X mental retardation syndrome-related protein 1 is ...
, which directly binds eIF4e at a domain that is structurally similar to those found in 4E-BPs including EIF4EBP3, EIF4EBP1, and EIF4EBP2. The FMRP/CYFIP1 complex binds in such a way as to prevent the eIF4E-eIF4G interaction, which is necessary for
translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
to occur. The FMRP/CYFIP1/eIF4E interaction is strengthened by the presence of
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
(s). In particular, BC1 RNA allows for an optimal interaction between FMRP and CYFIP1.
RNA-BC1 is a non-translatable,
dendritic
Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to:
Biology
*Dendrite, a branched projection of a neuron
*Dendrite (non-neuronal), branching projections of certain skin cells and immune cells
Physical
* Dendr ...
mRNA, which binds FMRP to allow for its association with a specific target mRNA. BC1 may function to regulate FMRP and mRNA interactions at
synapse(s) through its recruitment of FMRP to the appropriate mRNA.
In addition, FMRP may recruit CYFIP1 to specific mRNAs in order to repress translation. The FMRP-CYFIP1 translational inhibitor is regulated by stimulation of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
(s). Increased synaptic stimulation resulted in the dissociation of eIF4E and CYFIP1, allowing for the initiation of translation.
Interactions
EIF4E has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
EIF4A1
Eukaryotic initiation factor 4A-I (also known as eIF4A1 or DDX2A) is a 46 kDa cytosolic protein that, in humans, is encoded by the ''EIF4A1'' gene, which is located on chromosome 17. It is the most prevalent member of the eIF4A family of ATP-depe ...
,
*
EIF4EBP1
Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the ''EIF4EBP1'' gene.
Function
This gene encodes one member of a family of translation repressor proteins. The prot ...
,
* EIF4EBP2
Eukaryotic translation initiation factor 4E-binding protein 2 is a protein that in humans is encoded by the ''EIF4EBP2'' gene.
Animal studies
EIF4EBP2 knockout mice have been used as an animal model of autism. Mice without the Eif4ebp2 gene ...
,
* EIF4EBP3
Eukaryotic translation initiation factor 4E-binding protein 3 is a protein that in humans is encoded by the ''EIF4EBP3'' gene.
Function
This gene encodes a member of the EIF4EBP family which derives its name from proteins that bind to eukaryot ...
,
* EIF4ENIF1,
* EIF4G1
Eukaryotic translation initiation factor 4 gamma 1 is a protein that in humans is encoded by the ''EIF4G1'' gene.
Function
The protein encoded by this gene is a component of the protein complex eIF4F, which is involved in the recognition of the ...
, and
* EIF4G2
Eukaryotic translation initiation factor 4 gamma 2 (also called p97, NAT1, and DAP-5) is a protein that in humans is encoded by the ''EIF4G2'' gene.
Function
Translation initiation is mediated by specific recognition of the cap structure by euk ...
.
See also
* Eukaryotic initiation factor Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an i ...
s
* Eukaryotic initiation factor 4F (eIF4F)
References
Further reading
*
*
*
External links
Cap-dependent translation initiation
from ''Nature Reviews Microbiology
''Nature Reviews Microbiology'' is a monthly peer-reviewed review journal published by Nature Portfolio. It was established in 2003. The journal publishes reviews and perspectives on microbiology, bridging fundamental research and its clinical, in ...
''. A good image and overview of the function of initiation factors.
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