eIF2
Eukaryotic Initiation Factor 2 (eIF2) is an eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an alpha (also called subunit 1, EIF2S1), a beta (subunit 2, EIF2S2), and a gamma (subunit 3, EIF2S3) subunit.
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
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/4/45/Eukaryotic_initiation.png/400px-Eukaryotic_initiation.png)
eIF2 is an essential factor for protein synthesis that forms a ternary complex (TC) with GTP and the initiator Met-tRNAiMet. After its formation, the TC binds the 40S ribosomal subunit to form the 43S preinitiation complex (43S PIC). 43S PIC assembly is believed to be stimulated by the initiation factors eIF1, eIF1A, and the eIF3 complex according to in vitro experiments. The 43S PIC then binds mRNA that has previously been unwound by the eIF4F complex. The 43S PIC and the eIF4F proteins form a new 48S complex on the mRNA, which starts searching along the mRNA for the start codon (
Structure
[edit]eIF2 is a heterotrimer of a total molar mass of 126 kDa that is composed of the three sub-units:
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
The
The
Regulation
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/b/b3/EIF2regulation.jpg/300px-EIF2regulation.jpg)
eIF2 activity is regulated by a mechanism involving both guanine nucleotide exchange and phosphorylation. Phosphorylation takes place at the
Disease
[edit]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
[edit]- Eukaryotic initiation factors
- Kinases of eIF2
- eIF2A
- eIF2D
- Leukoencephalopathy with vanishing white matter
References
[edit]- ^ eIF2B consists of the sub-units EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
- ^ a b Kimball SR (1999). "Eukaryotic initiation factor eIF2". Int. J. Biochem. Cell Biol. 31 (1): 25–9. doi:10.1016/S1357-2725(98)00128-9. PMID 10216940.
- ^ a b c Hershey JW (1989). "Protein phosphorylation controls translation rates" (PDF). J. Biol. Chem. 264 (35): 20823–6. doi:10.1016/S0021-9258(19)30005-5. PMID 2687263.
- ^ a b c d Hinnebusch AG (2005). "Translational regulation of GCN4 and the general amino acid control of yeast". Annu. Rev. Microbiol. 59: 407–50. doi:10.1146/annurev.micro.59.031805.133833. PMID 16153175.
- ^ Kimball SR, Jefferson LS (2004). "Amino acids as regulators of gene expression". Nutr. Metab. 1 (1): 3. doi:10.1186/1743-7075-1-3. PMC 524028. 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". J. Biol. Chem. 279 (11): 10634–42. doi:10.1074/jbc.M310418200. PMID 14688270.
- ^ Ito T, Marintchev A, Wagner G (2004). "Solution structure of human initiation factor eIF2alpha reveals homology to the elongation factor eEF1B". Structure. 12 (9): 1693–704. doi:10.1016/j.str.2004.07.010. PMID 15341733.
- ^ Schmitt, E; Blanquet, S; Mechulam, Y (2 April 2002). "The large subunit of initiation factor aIF2 is a close structural homologue of elongation factors". The EMBO Journal. 21 (7): 1821–32. doi:10.1093/emboj/21.7.1821. PMC 125960. 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". J. Biol. Chem. 276 (2): 1051–6. doi:10.1074/jbc.M007398200. 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". Proc Natl Acad Sci USA. 76 (2): 600–4. Bibcode:1979PNAS...76..600S. doi:10.1073/pnas.76.2.600. PMC 382996. PMID 284384.
- ^ Hope A, Struhl K (1987). "GCN4, a eukaryotic transcriptional activator protein, binds as a dimer to target DNA". The EMBO Journal. 6 (9): 2781–2784. doi:10.1002/j.1460-2075.1987.tb02573.x. PMC 553703. PMID 3678204.
- ^ Knaap, Marjo S. van der; Pronk, Jan C.; Scheper, Gert C. (2006-05-01). "Vanishing white matter disease". The Lancet Neurology. 5 (5): 413–423. doi:10.1016/S1474-4422(06)70440-9. ISSN 1474-4422. PMID 16632312. S2CID 44301370.
- ^ Leegwater, Peter A. J.; Vermeulen, Gerre; Könst, Andrea A. M.; Naidu, Sakkubai; Mulders, Joyce; Visser, Allerdien; Kersbergen, Paula; Mobach, Dragosh; Fonds, Dafna; van Berkel, Carola G. M.; Lemmers, Richard J. L. F. (December 2001). "Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter". Nature Genetics. 29 (4): 383–388. doi:10.1038/ng764. ISSN 1546-1718. PMID 11704758. S2CID 20313523.
- ^ Chang RC, Yu MS, Lai CS (2006). "Significance of molecular signaling for protein translation control in neurodegenerative diseases". Neurosignals. 15 (5): 249–58. doi:10.1159/000102599. PMID 17496426.
External links
[edit]- 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