Published on None in volume None.

PubMed ID: 36357785

DOI: 10.1038/s41422-022-00741-8

Abstract:

N6-methyladenosine (m6A) is the most abundant and prevalent internal modification in mRNA.1 In mammals, m6A exerts pivotal roles in posttranscriptional regulation and its dysregulation is implicated in various diseases including cancer.2 m6A is installed by a multicomponent methyltransferase complex (MTC, also known as the m6A writer complex).3,4 The mammalian MTC is composed of the core m6A methyltransferase METTL3–METTL14 complex (MTC core) and several regulatory proteins including WTAP, the adaptor responsible for METTL3–METTL14 localization and proper substrate recruitment,5 and VIRMA (KIAA1429), the specificity mediator that mediates preferential m6A modification at the 3′ untranslated regions (UTRs, Fig. 1a).6 Dysregulation of MTC components results in the disruptions of m6A.2 Compared to the other currently identified regulators (HAKAI, ZC3H13 and RBM15), WTAP and VIRMA are reported to have greater impacts on total mRNA m6A levels upon knockdown.5,6 Despite the advances in understanding the roles of individual MTC components and the structural determination of MTC core,7,8,9 the overall molecular architecture of the m6A writer holocomplex is missing. Here, we report the cryogenic electron microscopy (cryo-EM) structure of human WTAP–VIRMA (3.1 Å) in the METTL3–METTL14–WTAP–VIRMA (M–M–W–V) complex and modeled a structure of the quaternary M–M–W–V complex based on AlphaFold2 predictions and structural restraints from intermolecular chemical crosslinking mass spectrometry (CXMS).