8d9l
From Proteopedia
Revision as of 07:41, 11 January 2023
CryoEM structure of human METTL1-WDR4 in complex with Lys-tRNA and SAM
Structural highlights
DiseaseWDR4_HUMAN Galloway-Mowat syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionWDR4_HUMAN Non-catalytic component of a methyltransferase complex required for the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs) (PubMed:12403464, PubMed:31031084, PubMed:31031083). In the methyltransferase complex, it is required to stabilize and induce conformational changes of the catalytic subunit (PubMed:12403464). Required for the formation of N(7)-methylguanine at position 46 (m7G46) in tRNA (PubMed:12403464, PubMed:31031084). Also required for the formation of N(7)-methylguanine at internal sites in a subset of mRNAs (PubMed:31031084). Also required for methylation of a specific subset of miRNAs, such as let-7 (PubMed:31031083). Independently of METTL1, also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1 (PubMed:26751069).[1] [2] [3] [4] Publication Abstract from PubMedSpecific, regulated modification of RNAs is important for proper gene expression(1,2). tRNAs are rich with various chemical modifications that affect their stability and function(3,4). 7-Methylguanosine (m(7)G) at tRNA position 46 is a conserved modification that modulates steady-state tRNA levels to affect cell growth(5,6). The METTL1-WDR4 complex generates m(7)G46 in humans, and dysregulation of METTL1-WDR4 has been linked to brain malformation and multiple cancers(7-22). 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 m(7)G 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 m(7)G modification by METTL1, providing the framework to understand its contribution to biology and disease. Structures and mechanisms of tRNA methylation by METTL1-WDR4.,Ruiz-Arroyo VM, Raj R, Babu K, Onolbaatar O, Roberts PH, Nam Y Nature. 2023 Jan 4. doi: 10.1038/s41586-022-05565-5. PMID:36599982[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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