Eukaryotic Initiation Factor 2 (eIF2) is an

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 imp ...

. It is required for most forms of eukaryotic

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 ''transl ...

initiation. eIF2 mediates the binding of

tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino a ...

_i^Met to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an

alpha Alpha (uppercase , lowercase ; grc, ἄλφα, ''álpha'', or ell, άλφα, álfa) is the first letter of the Greek alphabet. In the system of Greek numerals, it has a value of one. Alpha is derived from the Phoenician letter aleph , w ...

(also called subunit 1, EIF2S1), a

beta Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labi ...

(subunit 2, EIF2S2), and a

gamma Gamma (uppercase , lowercase ; ''gámma'') is the third letter of the Greek alphabet. In the system of Greek numerals it has a value of 3. In Ancient Greek, the letter gamma represented a voiced velar stop . In Modern Greek, this letter r ...

(subunit 3, EIF2S3) subunit. Once the initiation phase has completed, eIF2 is released from the ribosome bound to GDP as an inactive binary complex. To participate in another round of translation initiation, this GDP must be exchanged for GTP.

Function

eIF2 is an essential factor for protein synthesis that forms a ternary complex (TC) with GTP and the initiator Met-

_i^Met. After its formation, the TC binds the 40S ribosomal subunit to form the 43S preinitiation complex (43S PIC). 43S PIC assembly is believed to be stimulated by the initiation factors eIF1, eIF1A, and the eIF3 complex according to ''in vitro'' experiments. The 43S PIC then binds

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 t ...

that has previously been unwound by 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 ...

complex. The 43S PIC and the eIF4F proteins form a new 48S complex on the mRNA, which starts searching along the mRNA for the

start codon The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and Archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids. The m ...

(AUG). Upon base pairing of the AUG-codon with the Met-tRNA, eIF5 (which is a

GTPase-activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are ...

, or GAP) is recruited to the complex and induces eIF2 to hydrolyse its GTP. This causes eIF2-GDP to be released from this 48S complex and translation begins after recruitment of the 60S ribosomal subunit and formation of the 80S initiation complex. Finally, with the help of the

guanine nucleotide exchange factor Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated struct ...

(GEF)

eIF2B eIF2B is a protein complex found in eukaryotes. It is the guanine nucleotide exchange factor for the eukaryotic initiation factor 2 and therefore converts the inactive eIF2-GDP to the active eIF2- GTP. This activation is hindered by phosphorylat ...

, the GDP in eIF2 is exchanged for a GTP and the ternary complex reforms for a new round of translation initiation.

Structure

eIF2 is a heterotrimer of a total molar mass of 126 kDa that is composed of the three sub-units: α (sub-unit 1), β (sub-unit 2), and γ (sub-unit 3). The sequences of all three sub-units are highly conserved (pairwise amino acid identities for each sub-unit range from 47 to 72% when comparing the proteins of ''

Homo sapiens Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, a ...

'' and ''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been ...

''). The α-subunit contains the main target for

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

, a

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form ...

at position 51. It also contains a S1 motif domain, which is a potential RNA binding-site. Therefore, the α-subunit can be considered the regulatory subunit of the trimer. The β-subunit contains multiple phosphorylation sites (residues 2, 13, 67, 218). What is important to consider is that there are also three

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −CO ...

clusters in the N-terminal domain (NTD), which are important for the interaction with eIF2B. Moreover, the sequence of the protein comprises a zinc finger motif that was shown to play a role in both ternary complex and 43S preinitiation complex formation. There are also two guanine nucleotide-binding sequences that have not been shown to be involved in the regulation of eIF2 activity. The β-subunit is also believed to interact with both tRNA and mRNA. The γ-subunit comprises three guanine nucleotide-binding sites and is known to be the main docking site for GTP/GDP. It also contains a tRNA-binding cavity that has been shown by

X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

. A zinc knuckle motif is able to bind one Zn²⁺ cation. It is related to some elongation factors like

EF-Tu EF-Tu (elongation factor thermo unstable) is a prokaryotic elongation factor responsible for catalyzing the binding of an aminoacyl-tRNA (aa-tRNA) to the ribosome. It is a G-protein, and facilitates the selection and binding of an aa-tRNA to ...

Regulation

eIF2 activity is regulated by a mechanism involving both guanine nucleotide exchange and phosphorylation. Phosphorylation takes place at the α-subunit, which is a target for a number of serine kinases that phosphorylate

51. Those kinases act as a result of stress such as amino acid deprivation ( GCN2), ER stress ( PERK), the presence of dsRNA ( PKR) heme deficiency ( HRI), or

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten th ...

. Once phosphorylated, eIF2 shows increased affinity for eIF2B, its GEF. However, eIF2B is able to exchange GDP for GTP only if eIF2 is in its unphosphorylated state. Phosphorylated eIF2, however, due to its stronger binding, acts as an inhibitor of its own GEF (eIF2B). Since the cellular concentration of eIF2B is much lower than that of eIF2, even a small amount of phosphorylated eIF2 can completely abolish eIF2B activity by sequestration. Without the GEF, eIF2 can no longer be returned to its active (GTP-bound) state. As a consequence, translation comes to a halt since initiation is no longer possible without any available ternary complex. Furthermore, low concentration of ternary complex allows the expression of GCN4 (starved condition), which, in turn, results in increased activation of amino acid synthesis genes

Disease

Since eIF2 is essential for most forms of translation initiation and therefore protein synthesis, defects in eIF2 are often lethal. The protein is highly conserved among evolutionary remote species - indicating a large impact of mutations on cell viability. Therefore, no diseases directly related to mutations in eIF2 can be observed. However, there are many illnesses caused by down-regulation of eIF2 through its upstream kinases. For example, increased concentrations of active PKR and inactive (phosphorylated) eIF2 were found in patients with neurodegenerative diseases such as

Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

Parkinson's Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

, and Huntington's disease. There is also one proven example of a disease related to the GEF eIF2B. Mutations in all of the five subunits of eIF2B are associated with Vanishing White Matter (VWM) disease, a genetic leukodystrophy which causes the brain's white matter to degenerate and disappear. It is still not fully understood why only brain cells seem to be affected by these defects. Potentially reduced levels of unstable regulatory proteins might play a role in the development of the diseases mentioned.

References

External links