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Eukaryotic initiation factors (eIFs) are
proteins 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, re ...
or
protein complexes A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple catalytic domains are found in a single polypeptide chain. Protein c ...
involved in the initiation phase of
eukaryotic translation Eukaryotic translation is the biological process by which messenger RNA is Translation (biology), translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping. Initiation Translation init ...
. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start
codon Genetic code is a set of rules used by living cells to translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished by the ribosome, which links prote ...
and are an important input for post-transcription gene regulation. Several
initiation factor In molecular biology, initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of Translation (genetics), translation, a part of protein biosynthesis. Initiation factors can interact with repressors to ...
s form a complex with the small 40S ribosomal subunit and Met-
tRNA Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...
iMet called the 43S preinitiation complex (43S PIC). Additional factors of the
eIF4F Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the Five-prime cap, 5' cap of Messenger RNA, messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-i ...
complex (eIF4A, E, and G) recruit the 43S PIC to the
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 of the
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 Protein biosynthesis, synthesizing a protein. mRNA is ...
, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and
eIF1 Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the ''EIF1'' gene. It is related to yeast SUI1. eIF1 interacts with the eukaryotic small ( 40S) ribosomal subunit and eIF3, and is a component of the 43S ...
release to form the 48S preinitiation complex (48S PIC), followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.


eIF1 and eIF1A

eIF1 Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the ''EIF1'' gene. It is related to yeast SUI1. eIF1 interacts with the eukaryotic small ( 40S) ribosomal subunit and eIF3, and is a component of the 43S ...
and eIF1A both bind to the 40S ribosome subunit-mRNA complex. Together they induce an "open" conformation of the mRNA binding channel, which is crucial for scanning, tRNA delivery, and start codon recognition. In particular, eIF1 dissociation from the 40S subunit is considered to be a key step in start codon recognition. eIF1 and eIF1A are small proteins (13 and 16 kDa, respectively in humans) and are both components of the 43S PIC. eIF1 binds near the ribosomal P-site, while eIF1A binds near the
A-site The A-site (A for aminoacyl) of a ribosome is a binding site for charged t-RNA molecules during protein synthesis. One of three such binding sites, the A-site is the first location the t-RNA binds during the protein synthesis process, the othe ...
, in a manner similar to the structurally and functionally related bacterial counterparts IF3 and IF1, respectively.


eIF2

eIF2 is the main protein complex responsible for delivering the initiator tRNA to the P-site of the preinitiation complex, as a ternary complex containing Met-
tRNA Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...
iMet and GTP (the eIF2-TC). eIF2 has specificity for the methionine-charged initiator tRNA, which is distinct from other methionine-charged tRNAs used for elongation of the polypeptide chain. The eIF2 ternary complex remains bound to the P-site while the mRNA attaches to the 40s ribosome and the complex begins to scan the mRNA. Once the AUG start codon is recognized and located in the P-site, eIF5 stimulates the hydrolysis of eIF2-GTP, effectively switching it to the
GDP Gross domestic product (GDP) is a monetary measure of the total market value of all the final goods and services produced and rendered in a specific time period by a country or countries. GDP is often used to measure the economic performance o ...
-bound form via gated phosphate release. The hydrolysis of eIF2-GTP provides the conformational change to change the scanning complex into the 48S Initiation complex with the initiator tRNA-Met anticodon base paired to the AUG. After the initiation complex is formed the 60s subunit joins and eIF2 along with most of the initiation factors dissociate from the complex allowing the 60S subunit to bind. eIF1A and eIF5B-GTP remain bound to one another in the A site and must be hydrolyzed to be released and properly initiate elongation. eIF2 has three subunits, eIF2- α, β, and γ. The former α-subunit is a target of regulatory phosphorylation and is of particular importance for cells that may need to turn off protein synthesis globally as a response to
cell signaling In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...
events. When phosphorylated, it sequesters
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 ...
(not to be confused with eIF2β), a GEF. Without this GEF, GDP cannot be exchanged for GTP, and translation is repressed. One example of this is the eIF2α-induced translation repression that occurs in
reticulocytes In hematology, reticulocytes are immature red blood cells (RBCs). In the process of erythropoiesis (red blood cell formation), reticulocytes develop and mature in the bone marrow and then circulate for about a day in the blood stream before ...
when starved for iron. In the case of viral infection,
protein kinase R Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by ...
(PKR) phosphorylates eIF2α when
dsRNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself ( non-coding RNA) or by forming a template for the production of proteins ( messenger RNA). RNA and deoxy ...
is detected in many multicellular organisms, leading to cell death. The proteins
eIF2A Eukaryotic translation initiation factor 2A (eIF2A) is a protein that in humans is encoded by the ''EIF2A'' gene. The eIF2A protein is not to be confused with eIF2α, a subunit of the heterotrimeric eIF2 Eukaryotic Initiation Factor 2 (eIF2) is ...
and eIF2D are both technically named 'eIF2' but neither are part of the eIF2 heterotrimer and they seem to play unique functions in translation. Instead, they appear to be involved in specialized pathways, such as 'eIF2-independent' translation initiation or re-initiation, respectively.


eIF3

eIF3 Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of Eukaryotic translation#Cap-dependent initiation, cap-dependent and Eukaryotic ...
independently binds the 40S ribosomal subunit, multiple initiation factors, and cellular and viral mRNA. In mammals,
eIF3 Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of Eukaryotic translation#Cap-dependent initiation, cap-dependent and Eukaryotic ...
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 Ribosomes () are macromolecular machines, found within all cells, that perform biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA molecules to fo ...
subunit on mRNA that have a 5' cap or an IRES. eIF3 may use the
eIF4F Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the Five-prime cap, 5' cap of Messenger RNA, messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-i ...
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 The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
/ Raptor to effect translational regulation.


eIF4

The
eIF4F Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the Five-prime cap, 5' cap of Messenger RNA, messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-i ...
complex is composed of three subunits:
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 Messenger RNA, mRNA to 40S ribosome, ribosomal subunits. In addition these prot ...
, eIF4E, and eIF4G. Each subunit has multiple human isoforms and there exist additional eIF4 proteins: eIF4B and eIF4H. eIF4G is a 175.5-kDa scaffolding protein that interacts with
eIF3 Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of Eukaryotic translation#Cap-dependent initiation, cap-dependent and Eukaryotic ...
and the Poly(A)-binding protein (PABP), as well as the other members of the eIF4F complex. eIF4E recognizes and binds to the 5' cap structure of mRNA, while eIF4G binds PABP, which binds the
poly(A) tail Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...
, potentially circularizing and activating the bound mRNA. eIF4Aa DEAD box RNA
helicase Helicases are a class of enzymes that are 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 double helix, separating the two hybridized ...
is important for resolving mRNA secondary structures. eIF4B contains two RNA-binding domainsone non-specifically interacts with mRNA, whereas the second specifically binds the 18S portion of the small ribosomal subunit. It acts as an anchor, as well as a critical co-factor for eIF4A. It is also a substrate of S6K, and when phosphorylated, it promotes the formation of the pre-initiation complex. In vertebrates, eIF4H is an additional initiation factor with similar function to eIF4B.


eIF5, eIF5A and eIF5B

eIF5 Eukaryotic translation initiation factor 5 is a protein that in humans is encoded by the ''EIF5'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleoti ...
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 a ...
, which helps the large ribosomal subunit associate with the small subunit. It is required for GTP-hydrolysis by eIF2.
eIF5A Eukaryotic translation initiation factor 5A-1 is a protein that in humans is encoded by the ''EIF5A'' gene. It is the only known protein to contain the unusual amino acid hypusine 'N''ε-(4-amino-2-hydroxybutyl)-lysine which is synthesized on e ...
is the eukaryotic homolog of EF-P. It helps with elongation and also plays a role in termination. EIF5A contains the unusual amino acid
hypusine Hypusine is an uncommon amino acid found in all eukaryotes and in some archaea, but not in bacteria. The only known proteins containing the hypusine residue is eukaryotic translation initiation factor 5A (eIF-5A) and a similar protein found in ar ...
. eIF5B is a
GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a ...
, and is involved in assembly of the full ribosome. It is the functional eukaryotic analog of bacterial IF2.


eIF6

eIF6 performs the same inhibition of ribosome assembly as eIF3, but binds with the large subunit.


See also

*
Eukaryotic translation Eukaryotic translation is the biological process by which messenger RNA is Translation (biology), translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping. Initiation Translation init ...
* Ded1/DDX3 * DHX29


References


Further reading

* *


External links

* {{GeneticTranslation Helicases Molecular biology Protein biosynthesis Gene expression