National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01 GM122960
米国
Cancer Prevention and Research Institute of Texas (CPRIT)
RP190259
米国
Welch Foundation
I-2115-20220331
米国
引用
ジャーナル: Nature / 年: 2023 タイトル: Structures and mechanisms of tRNA methylation by METTL1-WDR4. 著者: Victor M Ruiz-Arroyo / Rishi Raj / Kesavan Babu / Otgonbileg Onolbaatar / Paul H Roberts / Yunsun Nam / 要旨: Specific, regulated modification of RNAs is important for proper gene expression. tRNAs are rich with various chemical modifications that affect their stability and function. 7-Methylguanosine (mG) ...Specific, regulated modification of RNAs is important for proper gene expression. tRNAs are rich with various chemical modifications that affect their stability and function. 7-Methylguanosine (mG) at tRNA position 46 is a conserved modification that modulates steady-state tRNA levels to affect cell growth. The METTL1-WDR4 complex generates mG46 in humans, and dysregulation of METTL1-WDR4 has been linked to brain malformation and multiple cancers. Here we show how METTL1 and WDR4 cooperate to recognize RNA substrates and catalyse methylation. A crystal structure of METTL1-WDR4 and cryo-electron microscopy structures of METTL1-WDR4-tRNA show that the composite protein surface recognizes the tRNA elbow through shape complementarity. The cryo-electron microscopy structures of METTL1-WDR4-tRNA with S-adenosylmethionine or S-adenosylhomocysteine along with METTL1 crystal structures provide additional insights into the catalytic mechanism by revealing the active site in multiple states. The METTL1 N terminus couples cofactor binding with conformational changes in the tRNA, the catalytic loop and the WDR4 C terminus, acting as the switch to activate mG methylation. Thus, our structural models explain how post-translational modifications of the METTL1 N terminus can regulate methylation. Together, our work elucidates the core and regulatory mechanisms underlying mG modification by METTL1, providing the framework to understand its contribution to biology and disease.