Structural insights into regulatory mechanism of RNA modification by human m6A-METTL associated complex

ABSTRACT: N6-methyladenosine (m6A) is the most abundant ribonucleotide modification among the eukaryotic messenger RNAs (mRNAs). The m6A “writer” is composed of an m6A-METTL complex (MAC), the catalytic subunit, and an m6A-METTL associated complex (MACOM), the regulatory subunit essential for the enzymatic activity. Here we report the cryo-electron microscopy (cryo-EM) structures of MACOM at 3.0-Å resolution, uncovering that WTAP and VIRMA form the core structure of MACOM and ZC3H13 stretches the conformation by binding VIRMA. The lower 4.4-Å resolution cryo-EM datamap of MACOM in complex with MAC, in combination with crosslinking mass spectrometry and GST-pulldown analysis, elucidates a plausible model of the m6A writer complex, in which MACOM binds MAC mainly through WTAP and METTL3 interaction and both components directly contact with RNA substrates revealed by 4-thiouridine-labeled RNA crosslinking analysis. This work establishes the possible assembly mechanism of MACOM and MAC as an active m6A writer for RNA substrate recognition and modification.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jinbiao Ma  

PROVIDER: PXD028456 | iProX | Thu Jun 23 00:00:00 BST 2022

REPOSITORIES: iProX