eIF2
Eukaryotic Initiation Factor 2 (eIF2) is an
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
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
sub-unit | Alpha | Beta | Gamma |
---|---|---|---|
Molecular Weight / kDa | 36 | 38 | 52 |
Similarity | eIF2-alpha family IPR011488 |
eIF2-beta / eIF5 family IPR002735 |
GTP-binding elongation factor family (and others) P41091 |
Interactions | Binding of eIF5, eIF2B and RNA | Binding of GTP and RNA |
The α-subunit contains the main target for phosphorylation, a serine 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
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. A zinc knuckle motif is able to bind one Zn2+ cation.[4][6][7] It is related to some elongation factors like EF-Tu.[8]
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
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, Parkinson's, 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.[12][13] 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.[4][14]
See also
- Eukaryotic initiation factors
- 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)
- eIF2A
- eIF2D
- Leukoencephalopathy with vanishing white matter
References
- ^ eIF2B consists of the sub-units EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
- ^ a b
Kimball SR (1999). "Eukaryotic initiation factor eIF2". PMID 10216940.
- ^ a b c
Hershey JW (1989). "Protein phosphorylation controls translation rates" (PDF). PMID 2687263.
- ^ a b c d
Hinnebusch AG (2005). "Translational regulation of GCN4 and the general amino acid control of yeast". PMID 16153175.
- ^
Kimball SR, Jefferson LS (2004). "Amino acids as regulators of gene expression". PMID 15507151.
- ^
Roll-Mecak A, Alone P, Cao C, Dever TE, Burley SK (2004). "X-ray structure of translation initiation factor eIF2gamma: implications for tRNA and eIF2alpha binding". PMID 14688270.
- ^
Ito T, Marintchev A, Wagner G (2004). "Solution structure of human initiation factor eIF2alpha reveals homology to the elongation factor eEF1B". PMID 15341733.
- PMID 11927566.
- ^ a b
Nika J, Rippel S, Hannig EM (2001). "Biochemical analysis of the eIF2beta gamma complex reveals a structural function for eIF2alpha in catalyzed nucleotide exchange". PMID 11042214.
- ^
Samuel CE (1979). "Mechanism of interferon action: Phosphorylation of protein synthesis initiation factor eIF-2 in interferon-treated human cells by a ribosome-associated kinase processing site specificity similar to hemin-regulated rabbit reticulocyte kinase". PMID 284384.
- ^
Hope A, Struhl K (1987). "GCN4, a eukaryotic transcriptional activator protein, binds as a dimer to target DNA". PMID 3678204.
- S2CID 44301370.
- S2CID 20313523.
- ^
Chang RC, Yu MS, Lai CS (2006). "Significance of molecular signaling for protein translation control in neurodegenerative diseases". PMID 17496426.
External links
- EIF-2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Cap-dependent translation initiation from Nature Reviews Microbiology. A good image and overview of the function of initiation factors