| Structural highlights
Disease
EFNMT_HUMAN METTL13 unregulation may be involved in tumorigenesis. High METTL13 expression has been observed in pancreatic and lung cancer tissues, correlates with overexpression of dimethylated elongation factor 1-alpha and is associated with poor clinical outcome. The disease mechanism involves dysregulation of mRNA translation and enhanced protein synthesis to sustain growth of malignant cells.[1]
Function
EFNMT_HUMAN Dual methyltransferase that catalyzes methylation of elongation factor 1-alpha (EEF1A1 and EEF1A2) at two different positions, and is therefore involved in the regulation of mRNA translation (PubMed:30612740, PubMed:30143613). Via its C-terminus, methylates EEF1A1 and EEF1A2 at the N-terminal residue 'Gly-2' (PubMed:30143613). Via its N-terminus dimethylates EEF1A1 and EEF1A2 at residue 'Lys-55' (PubMed:30612740, PubMed:30143613). Has no activity towards core histones H2A, H2B, H3 and H4 (PubMed:30612740). Negatively regulates cell proliferation at G1/S transition via transcriptional suppression of cell cycle regulatory genes such as CDK4 and CDK6 (PubMed:26763933).[2] [3] [4]
Publication Abstract from PubMed
Eukaryotic elongation factor 1 alpha (eEF1A) delivers aminoacyl-tRNA to the ribosome and thereby plays a key role in protein synthesis. Human eEF1A is subject to extensive post-translational methylation, but several of the responsible enzymes remain unknown. Using a wide range of experimental approaches, we here show that human methyltransferase (MTase)-like protein 13 (METTL13) contains two distinct MTase domains targeting the N terminus and Lys55 of eEF1A, respectively. Our biochemical and structural analyses provide detailed mechanistic insights into recognition of the eEF1A N terminus by METTL13. Moreover, through ribosome profiling, we demonstrate that loss of METTL13 function alters translation dynamics and results in changed translation rates of specific codons. In summary, we here unravel the function of a human MTase, showing that it methylates eEF1A and modulates mRNA translation in a codon-specific manner.
The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.,Jakobsson ME, Malecki JM, Halabelian L, Nilges BS, Pinto R, Kudithipudi S, Munk S, Davydova E, Zuhairi FR, Arrowsmith CH, Jeltsch A, Leidel SA, Olsen JV, Falnes PO Nat Commun. 2018 Aug 24;9(1):3411. doi: 10.1038/s41467-018-05646-y. PMID:30143613[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu S, Hausmann S, Carlson SM, Fuentes ME, Francis JW, Pillai R, Lofgren SM, Hulea L, Tandoc K, Lu J, Li A, Nguyen ND, Caporicci M, Kim MP, Maitra A, Wang H, Wistuba II, Porco JA Jr, Bassik MC, Elias JE, Song J, Topisirovic I, Van Rechem C, Mazur PK, Gozani O. METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis. Cell. 2019 Jan 24;176(3):491-504.e21. PMID:30612740 doi:10.1016/j.cell.2018.11.038
- ↑ Zhang Z, Zhang G, Kong C, Zhan B, Dong X, Man X. METTL13 is downregulated in bladder carcinoma and suppresses cell proliferation, migration and invasion. Sci Rep. 2016 Jan 14;6:19261. PMID:26763933 doi:10.1038/srep19261
- ↑ Jakobsson ME, Malecki JM, Halabelian L, Nilges BS, Pinto R, Kudithipudi S, Munk S, Davydova E, Zuhairi FR, Arrowsmith CH, Jeltsch A, Leidel SA, Olsen JV, Falnes PO. The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates. Nat Commun. 2018 Aug 24;9(1):3411. doi: 10.1038/s41467-018-05646-y. PMID:30143613 doi:http://dx.doi.org/10.1038/s41467-018-05646-y
- ↑ Liu S, Hausmann S, Carlson SM, Fuentes ME, Francis JW, Pillai R, Lofgren SM, Hulea L, Tandoc K, Lu J, Li A, Nguyen ND, Caporicci M, Kim MP, Maitra A, Wang H, Wistuba II, Porco JA Jr, Bassik MC, Elias JE, Song J, Topisirovic I, Van Rechem C, Mazur PK, Gozani O. METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis. Cell. 2019 Jan 24;176(3):491-504.e21. PMID:30612740 doi:10.1016/j.cell.2018.11.038
- ↑ Jakobsson ME, Malecki JM, Halabelian L, Nilges BS, Pinto R, Kudithipudi S, Munk S, Davydova E, Zuhairi FR, Arrowsmith CH, Jeltsch A, Leidel SA, Olsen JV, Falnes PO. The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates. Nat Commun. 2018 Aug 24;9(1):3411. doi: 10.1038/s41467-018-05646-y. PMID:30143613 doi:http://dx.doi.org/10.1038/s41467-018-05646-y
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