Function
mRNA capping enzyme (Mce) is a multifunctional protein with RNA triphosphatase, RNA guanylyltransferase, RNA methyltransferase and transcription factor activities. The 5' cap of mRNA is required for its stability and efficient translation. Mce activity entails the transfer of GMP from GTP to the 5'-diphosphate end of mRNA via a enzyme-(lysyl-GMP) intermediate by RNA triphosphatase and RNA guanylyltransferaseand finally the GpppRNA is converted to m7GpppRNA by RNA methyltransferase. In Vaccinia virus the active site is at Lys260 within the conserved motif KxDG in the catalytic subunit[1].
Relevance
Inhibition of Mce may provide a route for selecting therapeutic targeting of cancer cells which acquired deregulated c-Myc which is a potent driver of many human cancers[2]
Structural highlights
(PDB code 4ckb). The 3D structure of Vaccinia virus Mce shows the regulatory subunit or RNA triphosphatase domain which forms a hydrophilic tunnel. The . The structure shows the catalytic subunit or guanylyltransferase which contains the active site that binds the GTP via rich in basic residues[3].
- . Water molecule is shown as red sphere.
- (colored in royalblue), which are situated in GTP-binding site.
- .
- .
3D structures of mRNA capping enzyme
2c46 - hMce TPase domain 1-219 - human
3s24 - hMce GTase domain 229-567
1i9t, 1i9s - mMce TPase domain - mouse
3rtx - mMce GTase domain + DNA-dependent RNA polymerase II C-terminal + guanine
3kyh - yMce α+β subunits - yeast
4pz7 - fyMce α subunit - fission yeast
4pz8 - fyMce α subunit + SPT5
4pz6 - fyMce α subunit + DNA-dependent RNA polymerase II C terminal + GMP
4pn0 - fyMce β subunit
4pn1 - fyMce β subunit + SPT5 peptide
1p16 - Mce α subunit + GTP + RNA polymerase peptide - Candida albicans
1ri5 - EcMce - Encephalitozoon cuniculi
1ri4 - EcMce + SAM
1z3c - EcMce + SAM derivative
1ri3 - EcMce + SAH
1ri2 - EcMce + GTG
1ri1 - EcMce + SAH + GTG
1ckn, 1ckm - PbcvMce + GTP - Paramecium bursaria chlorella virus
1cko - PbcvMce + GPPPG
4cke, 4ckc, 2vdw - VvMce catalytic+regulatory subunits + SAH - Vaccinia virus
4ckb - VvMce catalytic+regulatory subunits + GTP + SAH
6rfl - VvMce catalytic+regulatory subunits + DNA-dependent RNA polymerase - Cryo EM
6rie - VvMce catalytic+regulatory subunits + DNA-dependent RNA polymerase + GDP + SAM - Cryo EM
5x6x - RdvMce - Rice dwarf virus
5x6z - RdvMce + GTP + GDP
5x71 - RdvMce + 5GP
5x6y - RdvMce + SAM
5x70 - RdvMce + RNA
8axv - cvMce – chikungunya virus – Cryo EM
8aov - cvMce + GTP – Cryo EM
7fgg - cvMce + 7GMP – Cryo EM
7fgh, 7fgi, 8aow - cvMce + SAH + 7GMP – Cryo EM
7y38 - cvMce + RNA polymerase + ATP + GTP – Cryo EM
7x01 - cvMce + inhibitor – Cryo EM
References
- ↑ Cong P, Shuman S. Mutational analysis of mRNA capping enzyme identifies amino acids involved in GTP binding, enzyme-guanylate formation, and GMP transfer to RNA. Mol Cell Biol. 1995 Nov;15(11):6222-31. doi: 10.1128/mcb.15.11.6222. PMID:7565775 doi:http://dx.doi.org/10.1128/mcb.15.11.6222
- ↑ Lombardi O, Varshney D, Phillips NM, Cowling VH. c-Myc deregulation induces mRNA capping enzyme dependency. Oncotarget. 2016 Dec 13;7(50):82273-82288. doi: 10.18632/oncotarget.12701. PMID:27756891 doi:http://dx.doi.org/10.18632/oncotarget.12701
- ↑ Kyrieleis OJ, Chang J, de la Pena M, Shuman S, Cusack S. Crystal structure of vaccinia virus mRNA capping enzyme provides insights into the mechanism and evolution of the capping apparatus. Structure. 2014 Mar 4;22(3):452-65. doi: 10.1016/j.str.2013.12.014. PMID:24607143 doi:http://dx.doi.org/10.1016/j.str.2013.12.014
