Eukaryotic initiation factor
Encyclopedia
Eukaryotic initiation factors (eIF) are proteins involved in the initiation phase of eukaryotic translation
. They function in forming a complex with the 40S
ribosomal subunit and Met-tRNAi called the 43S preinitation complex (PIC), recognizing the 5' cap structure of mRNA and recruiting the 43S PIC to mRNA, promoting ribosomal scanning of mRNA and regulating recognition of the AUG initiation codon, and joining of the 60S
ribosomal subunit to create the 80S ribosome
. There exist many more eukaryotic initiation factors than prokaryotic initiation factors
due to greater biological complexity of eukaryotic cells.
The protein RLI
is known to have an essential, probably catalytic role in the formation of initiation complexes as well.
, eIF4B
, eIF4E
, and eIF4G
. eIF4F is often used to refer to the complex of eIF4A, eIF4E, and eIF4G.
eIF4G is a scaffolding protein that interacts with eIF3 (see below), as well as the other members of the eIF4F complex. eIF4E recognizes and binds to the 5' cap structure of mRNA, while eIF4G binds to Poly(A)-binding protein
which binds the poly(A) tail, circularizing and activating the bound mRNA.
eIF4A a DEAD box
RNA helicase
is important for resolving mRNA secondary structures. eIF4B contains two RNA-binding domains one 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 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.
, eIF1A, and eIF3, all bind to the ribosome subunit-mRNA complex. They have been implicated in preventing the large ribosomal subunit from binding the small subunit before it is ready to commence elongation.
In mammals, eIF3 is the largest scaffolding initiation factor, made up of 13 subunits (a-m). It is roughly ~750 kDa and it controls the assembly of 40S
ribosomal
subunit on mRNA that have a 5' cap or an IRES. eIF3 uses the eIF4F complex or IRES (Internal Ribosomal Entry Site) from viruses to position the mRNA strand near the exit site of the 40S ribosome subunit, thus promoting the assembly of the pre-initiation complex.
In many cancers, eIF3 is overexpressed. Under serum-deprived conditions (inactive state), eIF3 is bound to S6K1. On stimulation either by mitogens, growth factors, or drugs, mTOR/Raptor complex gets activated and, in turn, binds and phosphorylates S6K1 on T389 (linker region), causing a conformational change that causes the kinase S6K1 to dissociate from eIF3. The T389 phosphorylated S6k1 is then further phosphorylated by PDK1 on T229. This second phosphorylation fully activates the S6K1 kinase, which can then phosphorylate eIF4B, S6 and other protein targets.
eIF2 is a GTP-binding protein responsible for bringing the initiator tRNA to the P-site of the pre-initiation complex. It has specificity for the methionine-charged initiator tRNA, which is distinct from other methionine-charged tRNAs specific for elongation of the polypeptide chain. Once it has placed the initiator tRNA on the AUG start codon in the P-site, it hydrolyzes GTP into GDP, and dissociates. This hydrolysis, also signals for the dissociation of eIF3, eIF1, and eIF1A, and allows the large subunit to bind. This signals the beginning of elongation.
eIF2 has three subunits, eIF2-α
, β
, and γ
. The former is of particular importance for cells that may need to turn off protein synthesis globally. When phosphorylated, it sequesters eIF2B (not to be confused with beta), a GEF. Without this GEF, GDP cannot be exchanged for GTP, and translation is repressed.
eIF2α-induced translation repression occurs in reticulocytes when starved for iron. In addition, protein kinase R
(PKR) phosphorylates eIF2α when dsRNA is detected in many multicellular organisms, leading to cell death.
is a GTPase-activating protein, which helps the large ribosomal subunit associate with the small subunit. It is required for GTP-hydrolysis by eIF2 and contains the unusual amino acid hypusine
.
eIF5B
is a GTPase
, and is involved in assembly of the full ribosome (which requires GTP hydrolysis).
performs the same inhibition of ribosome assembly as eIF3, but binds with the large subunit
.
Eukaryotic translation
Eukaryotic translation is the process by which messenger RNA is translated into proteins in eukaryotes. It consists of initiation, elongation and termination Translation-Initiation:-Cap-dependent initiation:...
. They function in forming a complex with the 40S
40S
40S is the small subunit of eukaryotic ribosomes.It interacts with the internal ribosome entry site of the hepatitis C virus.The following is a list of proteins contained in the 40S ribosome:...
ribosomal subunit and Met-tRNAi called the 43S preinitation complex (PIC), recognizing the 5' cap structure of mRNA and recruiting the 43S PIC to mRNA, promoting ribosomal scanning of mRNA and regulating recognition of the AUG initiation codon, and joining of the 60S
60S
60S is the large ribosomal subunit in eukaryotes. It corresponds to 50S in prokaryotes.It consists of the following:* 5S* 28S* 5.8SThe following is a list of proteins contained within the 60S ribosome:...
ribosomal subunit to create the 80S ribosome
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....
. There exist many more eukaryotic initiation factors than prokaryotic initiation factors
Prokaryotic initiation factors
Prokaryotes require the use of three initiation factors: IF1, IF2, and IF3, for translation.- IF1 :IF1 associates with the 30S ribosomal subunit in the A site and prevents an aminoacyl-tRNA from entering. It modulates IF2 binding to the ribosome by increasing its affinity. It may also prevent the...
due to greater biological complexity of eukaryotic cells.
The protein RLI
RLI
RLI is an essential and highly conserved protein that is required for both eukaryotic translation initiation as well as ribosome biogenesis. The most studied homologues are Rli1p in yeast and Pixie in Drosophila.-Structure:...
is known to have an essential, probably catalytic role in the formation of initiation complexes as well.
eIF4 (eIF4F)
The eIF4 initiation factors include eIF4AEif4a
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...
, eIF4B
EIF4B
Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the EIF4B gene.-External links:* from Nature Reviews Microbiology. A good image and overview of the function of initiation factors-Further reading:...
, eIF4E
EIF4E
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein which in humans is encoded by the eIF4E gene.- Function :...
, and eIF4G
EIF4G
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...
. eIF4F is often used to refer to the complex of eIF4A, eIF4E, and eIF4G.
eIF4G is a scaffolding protein that interacts with eIF3 (see below), as well as the other members of the eIF4F complex. eIF4E recognizes and binds to the 5' cap structure of mRNA, while eIF4G binds to Poly(A)-binding protein
Poly(A)-binding protein
Poly-binding protein is a RNA-binding protein which binds to the poly tail of mRNA. The poly tail is located on the 3' end of mRNA...
which binds the poly(A) tail, circularizing and activating the bound mRNA.
eIF4A a DEAD box
DEAD box
DEAD box proteins are involved in an assortment of metabolic processes that involve RNA. They are highly conserved in nine domains and can be found in both prokaryotes and eukaryotes, but not all...
RNA helicase
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...
is important for resolving mRNA secondary structures. eIF4B contains two RNA-binding domains one 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 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.
eIF1 & eIF3
eIF1EIF1
Eukaryotic translation initiation factor 1 is a protein that in humans is encoded by the EIF1 gene.-External links:* from Nature Reviews Microbiology. A good image and overview of the function of initiation factors-Further reading:...
, eIF1A, and eIF3, all bind to the ribosome subunit-mRNA complex. They have been implicated in preventing the large ribosomal subunit from binding the small subunit before it is ready to commence elongation.
In mammals, eIF3 is the largest scaffolding initiation factor, made up of 13 subunits (a-m). It is roughly ~750 kDa and it controls the assembly of 40S
40S
40S is the small subunit of eukaryotic ribosomes.It interacts with the internal ribosome entry site of the hepatitis C virus.The following is a list of proteins contained in the 40S ribosome:...
ribosomal
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....
subunit on mRNA that have a 5' cap or an IRES. eIF3 uses the eIF4F complex or IRES (Internal Ribosomal Entry Site) from viruses to position the mRNA strand near the exit site of the 40S ribosome subunit, thus promoting the assembly of the pre-initiation complex.
In many cancers, eIF3 is overexpressed. Under serum-deprived conditions (inactive state), eIF3 is bound to S6K1. On stimulation either by mitogens, growth factors, or drugs, mTOR/Raptor complex gets activated and, in turn, binds and phosphorylates S6K1 on T389 (linker region), causing a conformational change that causes the kinase S6K1 to dissociate from eIF3. The T389 phosphorylated S6k1 is then further phosphorylated by PDK1 on T229. This second phosphorylation fully activates the S6K1 kinase, which can then phosphorylate eIF4B, S6 and other protein targets.
eIF2
- See main article at EIF-2
eIF2 is a GTP-binding protein responsible for bringing the initiator tRNA to the P-site of the pre-initiation complex. It has specificity for the methionine-charged initiator tRNA, which is distinct from other methionine-charged tRNAs specific for elongation of the polypeptide chain. Once it has placed the initiator tRNA on the AUG start codon in the P-site, it hydrolyzes GTP into GDP, and dissociates. This hydrolysis, also signals for the dissociation of eIF3, eIF1, and eIF1A, and allows the large subunit to bind. This signals the beginning of elongation.
eIF2 has three subunits, eIF2-α
EIF2S1
Eukaryotic translation initiation factor 2 subunit 1 is a protein that in humans is encoded by the EIF2S1 gene.-Function:The protein encoded by this gene is the alpha subunit of the translation initiation factor eIF2 complex which catalyzes the first regulated step of protein synthesis initiation,...
, β
EIF2S2
Eukaryotic translation initiation factor 2 subunit 2 is a protein that in humans is encoded by the EIF2S2 gene.-Function:Eukaryotic translation initiation factor 2 functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA and binding to a 40S...
, and γ
EIF2S3
Eukaryotic translation initiation factor 2 subunit 3 is a protein that in humans is encoded by the EIF2S3 gene.-Function:Eukaryotic translation initiation factor 2 functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA and binding to a 40S...
. The former is of particular importance for cells that may need to turn off protein synthesis globally. When phosphorylated, it sequesters eIF2B (not to be confused with beta), a GEF. Without this GEF, GDP cannot be exchanged for GTP, and translation is repressed.
eIF2α-induced translation repression occurs in reticulocytes when starved for iron. In addition, protein kinase R
Protein kinase R
Protein kinase RNA-activated also known as protein kinase R , interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 is an enzyme that in humans is encoded by the EIF2AK2 gene.PKR protects against viral...
(PKR) phosphorylates eIF2α when dsRNA is detected in many multicellular organisms, leading to cell death.
eIF5 & eIF5B
eIF5AEIF5A
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 - -lysine], which is formed from the polyamine spermidine by two catalytic steps.-Further reading:...
is a GTPase-activating protein, which helps the large ribosomal subunit associate with the small subunit. It is required for GTP-hydrolysis by eIF2 and contains the unusual amino acid hypusine
Hypusine
Hypusine is an unusual amino acid found in all eukaryotes and in some archaea, but not in bacteria. The only known protein containing hypusine is eukaryotic translation initiation factor 5A and a similar protein found in archaebacteria. In humans, two isoforms of eIF-5A have been described:...
.
eIF5B
EIF5B
Eukaryotic translation initiation factor 5B is a protein that in humans is encoded by the EIF5B gene.-Further reading:...
is a GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
, and is involved in assembly of the full ribosome (which requires GTP hydrolysis).
eIF6
eIF6EIF6
Eukaryotic translation initiation factor 6 , also known as Integrin beta 4 binding protein , is a human gene....
performs the same inhibition of ribosome assembly as eIF3, but binds with the large subunit
60S
60S is the large ribosomal subunit in eukaryotes. It corresponds to 50S in prokaryotes.It consists of the following:* 5S* 28S* 5.8SThe following is a list of proteins contained within the 60S ribosome:...
.