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-Structure paper
タイトル | Structures and mechanisms of tRNA methylation by METTL1-WDR4. |
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ジャーナル・号・ページ | Nature, Vol. 613, Issue 7943, Page 383-390, Year 2023 |
掲載日 | 2023年1月4日 |
著者 | Victor M Ruiz-Arroyo / Rishi Raj / Kesavan Babu / Otgonbileg Onolbaatar / Paul H Roberts / Yunsun Nam / |
PubMed 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. |
リンク | Nature / PubMed:36599982 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 1.93 - 4.04 Å |
構造データ | EMDB-27264, PDB-8d9k: EMDB-27265, PDB-8d9l: EMDB-28108, PDB-8eg0: PDB-8d58: PDB-8d59: PDB-8d5b: |
化合物 | ChemComp-CL: ChemComp-IPA: ChemComp-GOL: ChemComp-HOH: ChemComp-SAM: ChemComp-SO4: ChemComp-CAC: ChemComp-SAH: |
由来 |
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キーワード | TRANSFERASE (転移酵素) / Cancer protein (悪性腫瘍) / Methyl transferase (メチルトランスフェラーゼ) / TRANSFERASE/RNA / TRANSFERASE-RNA complex |