Cap mRNA

Figure 38-7. Activation of elF-4E by insulin and formation of the cap binding elF-4F complex. The 4F-cap mRNA complex is depicted as in Figure 38-6. The 4F complex consists of elF-4E (4E), elF-4A, and elF-4G. 4E is inactive when bound by one ofa family of binding proteins (4E-BPs). Insulin and mitogenic factors (eg, IGF-1, PDGF, interleukin-2, and angiotensin II) activate a serine protein kinase in the mTOR pathway, and this results in the phosphorylation of 4E-BP. Phosphorylated 4E-BP dissociates from 4E, and the latter is then able to form the 4F complex and bind to the mRNA cap. These growth peptides also phosphorylate 4E itself by activating a component of the MAP kinase pathway. Phosphorylated 4E binds much more avidly to the cap than does nonphosphorylated 4E.

Ho CK, Shuman S. A yeast-like mRNA capping apparatus in Plasmodium falciparum. Proc Natl Acad Sci USA 2001 98[6] 3050-3055. 

The nature of the cap structure can also influence mRNA stability. The stability of mRNA capped with different ARCAs is determined in MM3MG cells that are electroporated with luciferase mRNAs containing a 60-nt poly(A) tract and different cap analogs. The experiment is done... 

Peng, Z.-H., Sharma, V., Singleton, S. F., and Gershon, P. D. (2002). Synthesis and application of a chain-terminating dinucleotide mRNA cap analog. Organic Letters 4, 161-164. 

Therefore, mRNA capping represents a potentially useful target for inhibitors with antifungal or antiviral activity indeed, whole-yeast cell-based assays developed to identify and characterize inhibitors of fungal mRNA capping allowed the identification and characterization of... 

Chrebet, G. L., Wisniewski, D., Perkins, A. L., Deng, Q., Kurtz, M. B., Marcy, A., and Parent, S. A. (2005). Cell-based assays to detect inhibitors of fungal mRNA capping enzymes and characterization of Sinefungin as a cap methyltransferase inhibitor.J. Biomol. Screen. 10, 355-364. 

Shuman, S. (2001). The mRNA capping apparatus as drug target and guide to eukaryotic phylogeny. Cold Spring Harb. Symp. Quant. Biol. 66, 301—312. 

Shen, X., Tomoo, K., Uchiyama, S., Kobayashi, Y., and Ishida, T. (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. (Tokyo) 49, 1299—1303. 

Tomoo, K., Matsushita, Y., Fujisaki, H., Abiko, F., Shen, X., Taniguchi, T., Miyagawa, H., Kitamura, K., Miura, K., and Ishida, T. (2005). Structural basis for mRNA cap-binding regulation of eukaryotic initiation factor 4E by 4E-binding protein, studied by spectroscopic, X-ray crystal structural, and molecular dynamics simulation methods. Biochim. Biophys. Acta 1753, 191—208. 

The process of translation can be divided into three stages initiation, elongation, and termination. Usually, the AUG codon next to the mRNA cap is used to initiate translation. It is thought that a 43 S preinitiation... 

L. Yu, A. Martins, L. Deng and S. Shuman (1997). Structure-function analysis of the triphosphatase component of vaccina virus mRNA capping enzyme. J. Virol., 71, 9837-9843. 

Li C, Gershon PD. pKa of the mRNA cap-specific 2 -0-methyl-transferase catalytic lysine by HSQC NMR detection of a two-carbon probe. Biochemistry 2006 45 907-917. 

Mature mRNA is formed by extensively modifying the primary transcript also called heterogeneous nuclear RNA (hnRNA). The hnRNA must undergo three major modifications before maturing into mRNA capping, polyadenylation and splicing. 

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