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The structure of the METTL3-METTL14 complex, which mediates N.sup.6-adenosine methylation of RNA, suggests that the METTL3 subunit is the catalytic core while METTL14 serves to bind RNA. A window on m.sup.6A epitranscriptomics The various base modifications now known to occur in messenger RNA and long non-coding RNA are reversible, and are utilized to dynamically modify the function of the RNA. The N.sup.6-methyladenosine modification is removed by an enzyme complex comprising METTL3 and METTL14. Ping Yin and colleagues have solved structures of the methyltransferase domains of this heterodimeric complex with and without ligand. Surprisingly, the S-adenosyl methionine ligand was found only the METTL3 pocket, not in METTL14. This suggests a model in which there is a single catalytic subunit, with METTL3 functioning as an RNA binding platform. The reported structures provide unprecedented mechanistic insight into m.sup.6A RNA methylation and suggest new opportunities for the development of therapeutic agents. Chemical modifications of RNA have essential roles in a vast range of cellular processes.sup.1,2,3. N.sup.6-methyladenosine (m.sup.6A) is an abundant internal modification in messenger RNA and long non-coding RNA that can be dynamically added and removed by RNA methyltransferases (MTases) and demethylases, respectively.sup.2,3,4,5. An MTase complex comprising methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) efficiently catalyses methyl group transfer.sup.6,7. In contrast to the well-studied DNA MTase.sup.8, the exact roles of these two RNA MTases in the complex remain to be elucidated. Here we report the crystal structures of the METTL3-METTL14 heterodimer with MTase domains in the ligand-free, S-adenosyl methionine (AdoMet)-bound and S-adenosyl homocysteine (AdoHcy)-bound states, with resolutions of 1.9, 1.71 and 1.61 Å, respectively. Both METTL3 and METTL14 adopt a class I MTase fold and they interact with each other via an extensive hydrogen bonding network, generating a positively charged groove. Notably, AdoMet was observed in only the METTL3 pocket and not in METTL14. Combined with biochemical analysis, these results suggest that in the m.sup.6A MTase complex, METTL3 primarily functions as the catalytic core, while METTL14 serves as an RNA-binding platform, reminiscent of the target recognition domain of DNA N.sup.6-adenine MTase.sup.9,10. This structural information provides an important framework for the functional investigation of m.sup.6A., Author(s): Xiang Wang [sup.1] , Jing Feng [sup.1] , Yuan Xue [sup.1] , Zeyuan Guan [sup.1] , Delin Zhang [sup.1] , Zhu Liu [sup.2] , Zhou Gong [sup.3] , Qiang [...]

Author(s): Xiang Wang; Jing Feng; Yuan Xue; Zeyuan Guan; Delin Zhang; Zhu Liu; Zhou Gong; Qiang Wang; Jinbo Huang; Chun Tang; Tingting Zou; Ping Yin Nature 534, 575578 (2016);doi:10.1038/nature18298 In [...]