The protein encoded by this gene is the alpha (α) subunit of the translation initiation factoreIF2 complex which catalyzes an early regulated step of protein synthesis initiation, promoting the binding of the initiator tRNA (Met-tRNAiMet) to 40Sribosomal subunits. Binding occurs as a ternary complex of methionyl-tRNA, eIF2, and GTP. eIF2 is composed of 3 nonidentical subunits, alpha (α, 36 kD, this article), beta (β, 38 kD), and gamma (γ, 52 kD). The rate of formation of the ternary complex is modulated by the phosphorylation state of eIF2α.[2]
Clinical significance
After reperfusion following brain ischemia, there is inhibition of neuron protein synthesis due to phosphorylation of eIF2α. There is colocalization between phosphorylated eIF2α and cytosoliccytochrome c, which is released from mitochondria in apoptosis. Phosphorylated Eif2-alpha appeared before cytochrome c release, suggesting that phosphorylation of eIF2α triggers cytochrome c release during apoptotic cell death.[3]
Mice heterozygous for the S51A mutation become obese and diabetic on a high-fat diet. Glucose intolerance resulted from reduced insulin secretion, defective transport of proinsulin, and a reduced number of insulin granules in beta cells. Hence proper functioning of eIF2α appears essential for preventing diet-induced type II diabetes.[4]
Dephosphorylation inhibitors
Salubrinal is a selective inhibitor of enzymes that dephosphorylate eIF2α.[5] Salubrinal also blocks eIF2α dephosphorylation by a herpes simplex virus protein and inhibits viral replication. eIF2α phosphorylation is cytoprotective during endoplasmic reticulum stress.[6][7]
↑Ernst H, Duncan RF, Hershey JW (Mar 1987). "Cloning and sequencing of complementary DNAs encoding the alpha-subunit of translational initiation factor eIF-2. Characterization of the protein and its messenger RNA". J Biol Chem. 262 (3): 1206–12. PMID2948954.
↑Page AB, Owen CR, Kumar R, Miller JM, Rafols JA, White BC, DeGracia DJ, Krause GS (July 2003). "Persistent eIF2alpha(P) is colocalized with cytoplasmic cytochrome c in vulnerable hippocampal neurons after 4 hours of reperfusion following 10-minute complete brain ischemia". Acta Neuropathol. 106 (1): 8–16. doi:10.1007/s00401-003-0693-2. PMID12687390.
↑Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, Ribick M, Schuit FC, Kaufman RJ (July 2005). "Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis". Nat. Med. 11 (7): 757–764. doi:10.1038/nm1259. PMID15980866.
↑Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J (February 2005). "A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress". Science. 307 (5711): 935–939. doi:10.1126/science.1101902. PMID15705855.
↑Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (May 2000). "Perk is essential for translational regulation and cell survival during the unfolded protein response". Mol. Cell. 5 (5): 897–904. doi:10.1016/S1097-2765(00)80330-5. PMID10882126.
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Mellor H, Proud CG (1991). "A synthetic peptide substrate for initiation factor-2 kinases". Biochem. Biophys. Res. Commun. 178 (2): 430–437. doi:10.1016/0006-291X(91)90125-Q. PMID1677563.
Green SR, Spalding A, Ashford T, et al. (1992). "Synthesis of human initiation factor-2 alpha in Saccharomyces cerevisiae". Gene. 108 (2): 253–258. doi:10.1016/0378-1119(91)90441-D. PMID1748310.
Ray MK, Chakraborty A, Datta B, et al. (1993). "Characteristics of the eukaryotic initiation factor 2 associated 67-kDa polypeptide". Biochemistry. 32 (19): 5151–5159. doi:10.1021/bi00070a026. PMID8098621.
Brand SR, Kobayashi R, Mathews MB (1997). "The Tat protein of human immunodeficiency virus type 1 is a substrate and inhibitor of the interferon-induced, virally activated protein kinase, PKR". J. Biol. Chem. 272 (13): 8388–8395. doi:10.1074/jbc.272.13.8388. PMID9079663.
Ting NS, Kao PN, Chan DW, et al. (1998). "DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45". J. Biol. Chem. 273 (4): 2136–2145. doi:10.1074/jbc.273.4.2136. PMID9442054.
Kimball SR, Heinzinger NK, Horetsky RL, Jefferson LS (1998). "Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B". J. Biol. Chem. 273 (5): 3039–3044. doi:10.1074/jbc.273.5.3039. PMID9446619.
Berlanga JJ, Santoyo J, De Haro C (1999). "Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase". Eur. J. Biochem. 265 (2): 754–762. doi:10.1046/j.1432-1327.1999.00780.x. PMID10504407.
Lu J, O'Hara EB, Trieselmann BA, et al. (1999). "The interferon-induced double-stranded RNA-activated protein kinase PKR will phosphorylate serine, threonine, or tyrosine at residue 51 in eukaryotic initiation factor 2alpha". J. Biol. Chem. 274 (45): 32198–32203. doi:10.1074/jbc.274.45.32198. PMID10542257.
