8EG0

CryoEM structure of human METTL1-WDR4 in complex with Lys-tRNA and SAH

Summary for 8EG0

• Entry DOI: 10.2210/pdb8eg0/pdb
• Related: 8D9K 8D9L
• EMDB information: 27264 27265 28108
• Descriptor: tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4, tRNA (guanine-N(7)-)-methyltransferase, RNA (65-MER), ... (4 entities in total)
• Functional Keywords: cancer protein, methyl transferase, transferase, transferase-rna complex, transferase/rna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 100186.15

Authors

Ruiz-Arroyo, V.M.,Nam, Y. (deposition date: 2022-09-10, release date: 2023-01-11, Last modification date: 2024-06-19)

Primary citation

Ruiz-Arroyo, V.M.,Raj, R.,Babu, K.,Onolbaatar, O.,Roberts, P.H.,Nam, Y.
Structures and mechanisms of tRNA methylation by METTL1-WDR4.
Nature, 613:383-390, 2023

PubMed Abstract: 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.

PubMed: 36599982
DOI: 10.1038/s41586-022-05565-5

Experimental method

ELECTRON MICROSCOPY (3.53 Å)