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, respo ...

protein complexes A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein ...

involved in the initiation phase of

eukaryotic translation Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: gene translation, elongation, termination, and recapping. Initiation Translation initiation is the pr ...

. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start

codon The genetic code is the 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 ...

and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small

40S The eukaryotic small ribosomal subunit (40S) is the smaller subunit of the eukaryotic 80S ribosomes, with the other major component being the large ribosomal subunit (60S). The "40S" and "60S" names originate from the convention that ribosomal pa ...

ribosomal subunit and Met-

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 ac ...

_i^Met called the

43S preinitiation complex The 43S preinitiation complex (43S PIC) is a ribonucleoprotein complex that exists during an early step of eukaryotic translation initiation. The 43S PIC contains the small ribosomal subunit (40S) bound by the initiation factors eIF1, eIF1A, eIF3 ...

(43S PIC). Additional factors 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- ...

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 o ...

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-tRNA_i^Met promotes gated phosphate and eIF1 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 Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis. Initiation factors can interact with repressors to slow down or prevent translation. They have the ...

than

prokaryotic initiation factors A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...

, 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 and

eIF1A Eukaryotic translation initiation factor 1A, X-chromosomal (eIF1A) is a protein that in humans is encoded by the ''EIF1AX'' gene. This gene encodes an essential eukaryotic translation initiation factor. The protein is a component of the 43S pre-in ...

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 The P-site (for peptidyl) is the second binding site for tRNA in the ribosome. The other two sites are the A-site (aminoacyl), which is the first binding site in the ribosome, and the E-site (exit), the third. During protein translation, the 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 other ...

, 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-

_i^Met 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 market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is ofte ...

-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 eIF5-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) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

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 phosphorylatio ...

(not to be confused with eIF2β), a

GEF Gef ( ), also referred to as the Talking Mongoose or the Dalby Spook, was the name given to an allegedly talking mongoose which was claimed to inhabit a farmhouse owned by the Irving family. The Irvings' farm was located at Cashen's Gap near ...

. 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 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 developing into ...

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 t ...

(PKR) phosphorylates eIF2α when

dsRNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

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 complex. Instead, eIF2A functions by a sepa ...

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 t ...

independently binds the

ribosomal subunit, multiple initiation factors, and cellular and viral mRNA. In mammals,

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

ribosomal Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to for ...

subunit on mRNA that have a 5' cap or an IRES. eIF3 may use the

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 Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of PIP3 ...

and

mTOR The mammalian target of sirolimus, 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 ''MT ...

Raptor Raptor or RAPTOR may refer to: Animals The word "raptor" refers to several groups of bird-like dinosaurs which primarily capture and subdue/kill prey with their talons. * Raptor (bird) or bird of prey, a bird that primarily hunts and feeds on ...

to effect translational regulation.

eIF4

The

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 mRNA to 40S ribosomal subunits. In addition these proteins are helicases that f ...

eIF4E Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the ''EIF4E'' gene. Structure and function Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine fi ...

, and

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, yeast ...

. Each subunit has multiple human isoforms and there exist additional eIF4 proteins:

eIF4B Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the ''EIF4B'' gene. Interactions eIF4B has been shown to interact with and stimulate the activity of eIF4A and bind to the eIF3 complex through the eIF3A subu ...

and

eIF4H Eukaryotic translation initiation factor 4H is a protein that in humans is encoded by the ''EIF4H'' gene. This gene encodes one of the translation initiation factors, which function to stimulate the initiation of protein synthesis at the level of ...

. eIF4G is a 175.5-kDa scaffolding protein that interacts with

and the

Poly(A)-binding protein Poly(A)-binding protein (PAB or PABP) is an RNA-binding protein which triggers the binding of eukaryotic initiation factor 4 complex (eIF4G) directly to the poly(A) tail of mRNA which is 200-250 nucleotides long. The poly(A) tail is located on th ...

(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 euk ...

, potentially circularizing and activating the bound mRNA. eIF4Aa

DEAD box Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

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 ...

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 (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ...

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 ...

, 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 ...

eIF5B Eukaryotic translation initiation factor 5B is a protein that in humans is encoded by the ''EIF5B'' gene. Accurate initiation of translation in eukaryotes is complex and requires many factors, some of which are composed of multiple subunits. The ...

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 pro ...

, and is involved in assembly of the full ribosome. It is the functional eukaryotic analog of bacterial IF2.

eIF6

eIF6 Eukaryotic translation initiation factor 6 (EIF6), also known as Integrin beta 4 binding protein (ITGB4BP), is a human gene. Hemidesmosomes are structures which link the basal lamina to the intermediate filament cytoskeleton. An important functio ...

performs the same inhibition of ribosome assembly as eIF3, but binds with the

large subunit In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "''coassembles''") with others to form a protein complex. Large assemblies of proteins such as viruses often use a small number of ty ...

References

External links

* {{GeneticTranslation Molecular biology Protein biosynthesis Gene expression