EIF2S1
Eukaryotic translation initiation factor 2 subunit 1 (eIF2α) is a protein that in humans is encoded by the EIF2S1 gene.[5][6]
Function
The protein encoded by this gene is the alpha (α) subunit of the translation initiation factor eIF2 protein complex which catalyzes an early regulated step of protein synthesis initiation, promoting the binding of the initiator tRNA (Met-tRNAiMet) to 40S ribosomal 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.[6] Phosphorylation of eIF2α by EIF-2 kinases plays a key role in regulating the integrated stress response.[7]
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 cytosolic cytochrome 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.[8]
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.[9]
Dephosphorylation inhibitors
Salubrinal is a selective inhibitor of enzymes that dephosphorylate eIF2α.[10] Salubrinal also blocks eIF2α dephosphorylation by a herpes simplex virus protein and inhibits viral replication. eIF2α phosphorylation is cytoprotective during endoplasmic reticulum stress.[11][12]
See also
References
- GRCh38: Ensembl release 89: ENSG00000134001 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000021116 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Ernst H, Duncan RF, Hershey JW (January 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". The Journal of Biological Chemistry. 262 (3): 1206–12. PMID 2948954.
- "Entrez Gene: EIF2S1 eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa". National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 2010-10-05.
- Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM (October 2016). "The integrated stress response". EMBO Reports. 17 (10): 1374–1395. doi:10.15252/embr.201642195. PMC 5048378. PMID 27629041.
- Page AB, Owen CR, Kumar R, Miller JM, Rafols JA, White BC, et al. (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 Neuropathologica. 106 (1): 8–16. doi:10.1007/s00401-003-0693-2. PMID 12687390.
- Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, et al. (July 2005). "Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis". Nature Medicine. 11 (7): 757–64. doi:10.1038/nm1259. PMID 15980866.
- Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, et al. (February 2005). "A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress". Science. 307 (5711): 935–9. doi:10.1126/science.1101902. PMID 15705855.
- 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". Molecular Cell. 5 (5): 897–904. doi:10.1016/S1097-2765(00)80330-5. PMID 10882126.
- Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, et al. (June 2001). "Translational control is required for the unfolded protein response and in vivo glucose homeostasis". Molecular Cell. 7 (6): 1165–76. doi:10.1016/S1097-2765(01)00265-9. PMID 11430820.
Further reading
- Hershey JW (1991). "Translational control in mammalian cells". Annual Review of Biochemistry. 60: 717–55. doi:10.1146/annurev.bi.60.070191.003441. PMID 1883206.
- Mao X, Green JM, Safer B, Lindsten T, Frederickson RM, Miyamoto S, et al. (October 1992). "Regulation of translation initiation factor gene expression during human T cell activation". The Journal of Biological Chemistry. 267 (28): 20444–50. PMID 1400363.
- Mellor H, Proud CG (July 1991). "A synthetic peptide substrate for initiation factor-2 kinases". Biochemical and Biophysical Research Communications. 178 (2): 430–7. doi:10.1016/0006-291X(91)90125-Q. PMID 1677563.
- Green SR, Spalding A, Ashford T, Proud CG, Tuite MF (December 1991). "Synthesis of human initiation factor-2 alpha in Saccharomyces cerevisiae". Gene. 108 (2): 253–8. doi:10.1016/0378-1119(91)90441-D. PMID 1748310.
- Kramer G (July 1990). "Two phosphorylation sites on eIF-2 alpha". FEBS Letters. 267 (2): 181–2. doi:10.1016/0014-5793(90)80919-A. PMID 2116318.
- Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, et al. (December 1994). "Construction of a human full-length cDNA bank". Gene. 150 (2): 243–50. doi:10.1016/0378-1119(94)90433-2. PMID 7821789.}}
- Ray MK, Chakraborty A, Datta B, Chattopadhyay A, Saha D, Bose A, et al. (May 1993). "Characteristics of the eukaryotic initiation factor 2 associated 67-kDa polypeptide". Biochemistry. 32 (19): 5151–9. doi:10.1021/bi00070a026. PMID 8098621.}}
- Dever TE, Chen JJ, Barber GN, Cigan AM, Feng L, Donahue TF, et al. (May 1993). "Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast". Proceedings of the National Academy of Sciences of the United States of America. 90 (10): 4616–20. doi:10.1073/pnas.90.10.4616. PMC 46563. PMID 8099443.}}
- Barber GN, Wambach M, Wong ML, Dever TE, Hinnebusch AG, Katze MG (May 1993). "Translational regulation by the interferon-induced double-stranded-RNA-activated 68-kDa protein kinase". Proceedings of the National Academy of Sciences of the United States of America. 90 (10): 4621–5. doi:10.1073/pnas.90.10.4621. PMC 46564. PMID 8099444.}}
- Miyamoto S, Chiorini JA, Urcelay E, Safer B (May 1996). "Regulation of gene expression for translation initiation factor eIF-2 alpha: importance of the 3' untranslated region". The Biochemical Journal. 315 ( Pt 3) (3): 791–8. doi:10.1042/bj3150791. PMC 1217276. PMID 8645159.
- Yang W, Hinnebusch AG (November 1996). "Identification of a regulatory subcomplex in the guanine nucleotide exchange factor eIF2B that mediates inhibition by phosphorylated eIF2". Molecular and Cellular Biology. 16 (11): 6603–16. doi:10.1128/MCB.16.11.6603. PMC 231662. PMID 8887689.
- Brand SR, Kobayashi R, Mathews MB (March 1997). "The Tat protein of human immunodeficiency virus type 1 is a substrate and inhibitor of the interferon-induced, virally activated protein kinase, PKR". The Journal of Biological Chemistry. 272 (13): 8388–95. doi:10.1074/jbc.272.13.8388. PMID 9079663.
- Ting NS, Kao PN, Chan DW, Lintott LG, Lees-Miller SP (January 1998). "DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45". The Journal of Biological Chemistry. 273 (4): 2136–45. doi:10.1074/jbc.273.4.2136. PMID 9442054.| doi-access = free }}
- Kimball SR, Heinzinger NK, Horetsky RL, Jefferson LS (January 1998). "Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B". The Journal of Biological Chemistry. 273 (5): 3039–44. doi:10.1074/jbc.273.5.3039. PMID 9446619.
- Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC (December 1998). "Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control". Molecular and Cellular Biology. 18 (12): 7499–509. doi:10.1128/MCB.18.12.7499. PMC 109330. PMID 9819435.}}
- Satoh S, Hijikata M, Handa H, Shimotohno K (August 1999). "Caspase-mediated cleavage of eukaryotic translation initiation factor subunit 2alpha". The Biochemical Journal. 342 ( Pt 1) (1): 65–70. doi:10.1042/0264-6021:3420065. PMC 1220437. PMID 10432301.
- Berlanga JJ, Santoyo J, De Haro C (October 1999). "Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase". European Journal of Biochemistry. 265 (2): 754–62. doi:10.1046/j.1432-1327.1999.00780.x. PMID 10504407.
- Lu J, O'Hara EB, Trieselmann BA, Romano PR, Dever TE (November 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". The Journal of Biological Chemistry. 274 (45): 32198–203. doi:10.1074/jbc.274.45.32198. PMID 10542257.| doi-access = free }}
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