All eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosinefive-prime cap structure, m7GpppX (where X is any nucleotide). This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. eIF4E is a eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs. It is a 24-kD polypeptide that exists as both a free form and as part of the eIF4F pre-initiation complex. Almost all cellular mRNA require eIF4E in order to be translated into protein. The eIF4E polypeptide is the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis.
Some viruses cut eIF4G in such a way that the eIF4E binding site is removed and the virus is able to translate its proteins without eIF4E. Also some cellular proteins, the most notable being heat shock proteins, do not require eIF4E in order to be translated. Both viruses and cellular proteins achieve this through an internal ribosome entry site in the RNA.
FMRP represses translation through EIF4E binding
Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E. FMRP acts by binding CYFIP1, which directly binds eIF4e at a domain that is structurally similar to those found in 4E-BPs including EIF4EBP3, EIF4EBP1, and EIF4EBP2. The FMRP/CYFIP1 complex binds in such a way as to prevent the eIF4E-eIF4G interaction, which is necessary for translation to occur. The FMRP/CYFIP1/eIF4E interaction is strengthened by the presence of mRNA(s). In particular, BC1 RNA allows for an optimal interaction between FMRP and CYFIP1. RNA-BC1 is a non-translatable, dendritic mRNA, which binds FMRP to allow for its association with a specific target mRNA. BC1 may function to regulate FMRP and mRNA interactions at synapse(s) through its recruitment of FMRP to the appropriate mRNA.
In addition, FMRP may recruit CYFIP1 to specific mRNAs in order to repress translation. The FMRP-CYFIP1 translational inhibitor is regulated by stimulation of neuron(s). Increased synaptic stimulation resulted in the dissociation of eIF4E and CYFIP1, allowing for the initiation of translation.
^Pelletier J, Brook JD, Housman DE (August 1991). "Assignment of two of the translation initiation factor-4E (EIF4EL1 and EIF4EL2) genes to human chromosomes 4 and 20". Genomics10 (4): 1079–82. doi:10.1016/0888-7543(91)90203-Q. PMID1916814.
^Jones RM, MacDonald ME, Branda J, Altherr MR, Louis DN, Schmidt EV (May 1997). "Assignment of the human gene encoding eukaryotic initiation factor 4E (EIF4E) to the region q21-25 on chromosome 4". Somatic Cell and Molecular Genetics23 (3): 221–223. doi:10.1007/BF02721373. PMID9330633.
^Hutchins AP, Roberts GR, Lloyd CW, Doonan JH (2004). "In vivo interaction between CDKA and eIF4A: a possible mechanism linking translation and cell proliferation". FEBS Lett.556 (1-3): 91–4. doi:10.1016/S0014-5793(03)01382-6. PMID14706832.
^ abNapoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C (September 2008). "The Fragile X Syndrome Protein Represses Activity-Dependent Translation through CYFIP1, a New 4E-BP". Cell134 (6): 1042–1054. doi:10.1016/j.cell.2008.07.031. PMID18805096.
^Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C (February 2003). "The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses". Cell112 (3): 317–27. doi:10.1016/S0092-8674(03)00079-5. PMID12581522.
^Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature437 (7062): 1173–8. doi:10.1038/nature04209. PMID16189514.
^Eguchi S, Tokunaga C, Hidayat S, Oshiro N, Yoshino K, Kikkawa U, Yonezawa K (July 2006). "Different roles for the TOS and RAIP motifs of the translational regulator protein 4E-BP1 in the association with raptor and phosphorylation by mTOR in the regulation of cell size". Genes Cells11 (7): 757–66. doi:10.1111/j.1365-2443.2006.00977.x. PMID16824195.
^Yang D, Brunn GJ, Lawrence JC (June 1999). "Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR". FEBS Lett.453 (3): 387–90. doi:10.1016/s0014-5793(99)00762-0. PMID10405182.
^Patel J, McLeod LE, Vries RG, Flynn A, Wang X, Proud CG (June 2002). "Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors". Eur. J. Biochem.269 (12): 3076–85. doi:10.1046/j.1432-1033.2002.02992.x. PMID12071973.
^ abKumar V, Sabatini D, Pandey P, Gingras AC, Majumder PK, Kumar M, Yuan ZM, Carmichael G, Weichselbaum R, Sonenberg N, Kufe D, Kharbanda S (April 2000). "Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase". J. Biol. Chem.275 (15): 10779–87. doi:10.1074/jbc.275.15.10779. PMID10753870.
^Shen X, Tomoo K, Uchiyama S, Kobayashi Y, Ishida T (October 2001). "Structural and thermodynamic behavior of eukaryotic initiation factor 4E in supramolecular formation with 4E-binding protein 1 and mRNA cap analogue, studied by spectroscopic methods". Chem. Pharm. Bull.49 (10): 1299–303. doi:10.1248/cpb.49.1299. PMID11605658.
^Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Sonenberg N (October 1994). "Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function". Nature371 (6500): 762–7. doi:10.1038/371762a0. PMID7935836.
^Poulin F, Gingras AC, Olsen H, Chevalier S, Sonenberg N (May 1998). "4E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family". J. Biol. Chem.273 (22): 14002–7. doi:10.1074/jbc.273.22.14002. PMID9593750.
Culjkovic B, Topisirovic I, Borden KL (2007). "Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E". Cell Cycle6 (1): 65–9. doi:10.4161/cc.6.1.3688. PMID17245113.
Malys N, McCarthy JE (2010). "Translation initiation: variations in the mechanism can be anticipated". Cellular and Molecular Life Sciences68 (6): 991–1003. doi:10.1007/s00018-010-0588-z. PMID21076851.