EIF2

eIF2 (Eukaryotic Initiation Factor 2) is an eukaryotic initiation factor. It is required in the initiation of translation. In this fundamental process of life, the ribosome builds proteins according to the information encoded on the mRNA. eIF2 mediates the binding of tRNA^met to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an alpha (also called subunit 1), a beta (subunit 2), and a gamma (subunit 3) subunit.

Once the initiation is 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-tRNA. After its formation the TC binds the 40S ribosomal subunit to form the 43S preinitiation complex (PIC). PIC-assembly is believed to be stimulated by the initiation factors eIF1, eIF2A and the eIF3 complex according to "in vitro" experiments. The 43S PIC then binds mRNA that has previously been unwound by the eIF4s. The 43S PIC and the eIF4 proteins form a new 48S complex on the mRNA which starts searching along the mRNA for the start codon (AUG). Upon base pairing of the AUG-codon with the Met-tRNA, eIF5 (which is a GTPase activating protein) is recruited to the complex and induces eIF2 to hydrolyse its GTP. This causes eIF2-GDPto 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 eIF2B [eIF2B consists of the subunits
EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5] , the GDP in eIF2 is exchanged for a GTP and the ternary complex reforms for a new round of translation initiation.cite journal
author=Kimball SR
title=Eukaryotic initiation factor eIF2
journal=Int. J. Biochem. Cell Biol.
volume=31
issue=1
pages=25–9
year=1999
month=January
pmid=10216940
doi=
url=http://linkinghub.elsevier.com/retrieve/pii/S1357-2725(98)00128-9] cite journal
author=Hershey JW
title=Protein phosphorylation controls translation rates
journal=J. Biol. Chem.
volume=264
issue=35
pages=20823–6
year=1989
month=December
pmid=2687263
doi=
url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2687263] cite journal
author=Hinnebusch AG
title=Translational regulation of GCN4 and the general amino acid control of yeast
journal=Annu. Rev. Microbiol.
volume=59
issue=
pages=407–50
year=2005
pmid=16153175
doi=10.1146/annurev.micro.59.031805.133833
url=]

tructure

eIF2 is a heterotrimer of a total molar mass of 126 kDa that is composed of the three subunits α (subunit 1), β (subunit 2), and γ (subunit 3). The sequences of all three subunits are highly conserved (pairwise amino acid identities for each subunit range from 47 – 72 % when comparing the proteins of "Homo sapiens" and "Saccharomyces cerevisiae").

The α-subunit contains the main target for phosphorylation, a serine at position 51. It also contains a S1motif domain, which is a potential RNA binding-site. Therefore the α-subunit can be considered theregulatory subunit of the trimer.

The β-subunit contains multiple phosphorylation sites (residues 2, 13, 67, 218). More importantly thereare also three lysine clusters in the N-terminal domain (NTD) which are important for the interactionwith eIF2B. Moreover the sequence of the protein comprises a zinc finger motif which was shown to play a role in both ternary complex and 43S preinitiation complex formation. There are also two guanine nucleotide bindingsequences which 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 dockingsite for GTP/GDP. It also contains a tRNA binding cavity which has been shown by X-ray crystallography. A zinc knuckle motif is able to bind one Zn²⁺ cation.cite journal
author=Roll-Mecak A, Alone P, Cao C, Dever TE, Burley SK
title=X-ray structure of translation initiation factor eIF2gamma: implications for tRNA and eIF2alpha binding
journal=J. Biol. Chem.
volume=279
issue=11
pages=10634–42
year=2004
month=March
pmid=14688270
doi=10.1074/jbc.M310418200
url=] cite journal
author=Ito T, Marintchev A, Wagner G
title=Solution structure of human initiation factor eIF2alpha reveals homology to the elongation factor eEF1B
journal=Structure
volume=12
issue=9
pages=1693–704
year=2004
month=September
pmid=15341733
doi=10.1016/j.str.2004.07.010
url=]

Regulation

[
thumb|right|300px|Regulation_of_translation_initiation_via_phosphorylation_of_Ser51_in_eIF2cite journal
author=Nika J, Rippel S, Hannig EM
title=Biochemical analysis of the eIF2beta gamma complex reveals a structural function for eIF2alpha in catalyzed nucleotide exchange
journal=J. Biol. Chem.
volume=276
issue=2
pages=1051–6
year=2001
month=January
pmid=11042214
doi=10.1074/jbc.M007398200
url=] .] 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 serine 51. Those kinases act as a result of stress such asamino acid deprivation (GCN2), ER stress (PERK), the presence of dsRNA ( PKR) or Hemoglobin deficiency (HRI). Once phosphorylated, eIF2 shows increased affinity for its
Guanine nucleotide exchange factor eIF2B. However, eIF2B is only able to exchange GDP for GTP if eIF2 is in its unphosphorylatedstate. Phosphorylated eIF2, though, due 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 ofphosphorylated eIF2 can completely abolish eIF2B activity by sequestration. Without the GEF, eIF2can no longer be returned to its active (GTP-bound) state. Consequently translation comes to a halt sinceinitiation is no longer possible without any available ternary complex.

Disease

Since eIF2 is essential for translation initiation and therefore protein synthesis, defects in eIF2 are lethal. The protein is highly conserved among evolutionary remote species - indicating a large impact of mutations on cellviability. 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. Forexample, increased concentrations of active PKR and inactive (phosphorylated) eIF2 were found inpatients suffering from neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease. There is also one proven example of a disease related to the GEF eIF2B. Mutations in all of thefive subunits of eIF2B could be linked with leukoencephalopathy, an illness that causes the brain’swhite matter to disappear. It is still not fully understood why only brain cells seem to be affected bythese defects. Potentially reduced levels of unstable regulatory proteins might play a role in thedevelopment of the diseases mentioned.cite journal
author=Chang RC, Yu MS, Lai CS
title=Significance of molecular signaling for protein translation control in neurodegenerative diseases
journal=Neurosignals
volume=15
issue=5
pages=249–58
year=2006
pmid=17496426
doi=10.1159/000102599
url=]

ee also

* Eukaryotic initiation factors
* The three subunits of eIF2:
** α – EIF2S1
** β – EIF2S2
** γ – EIF2S3
* Kinases of eIF2
** HRI (Heme-regulated inhibitor kinase) or EIF2AK1
** PKR (Protein kinase R)
** PERK (PKR-like ER-localized eIF2α kinase)
** GCN2 (eukaryotic translation initiation factor 2 alpha kinase 4)
* GEF EIF2B (consists of the subunits EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5)
* GAP EIF5

References

External links

*
* [http://www.nature.com/nrmicro/journal/v5/n1/box/nrmicro1558_BX1.html Cap-dependent translation initiation] from Nature Reviews Microbiology. A good image and overview of the function of initiation factors