Structures of the m(6)A Methyltransferase Complex: Two Subunits with Distinct but Coordinated Roles

Abstract

In this issue of Molecular Cell, Wang et al. (2016a) report crystal structures of the core of the METTL3/METTL14 m(6)A methyltransferase complex and propose how the two subunits interact and cooperate to bind and methylate RNA.

Figure 1. Model of the core m⁶A methyltransferase complex

The salient features are: (1) The m⁶A methyltransferase catalytic site (indicated by yellow star) is located in the METTL3 methyltransferase domain (MTD). The catalytic cavity of METTL3 (DPPW motif) has an open conformation and binds the cofactor S-adenosylmethionine (SAM). In contrast, the putative catalytic cavity of METTL14 (EPPL motif) adopts a closed conformation. (2) METTL3 and METTL14 interact extensively in the m⁶A methyltransferase complex. The methyltransferase domains of METTL3 and METTL14 share a 2460 Ų interface, an additional helix in METTL14 interacts with the METTL3 MTD, and one of the fence loops surrounding the METTL3 catalytic site makes contacts with METTL14. (3) The putative RNA binding site, which specifically binds the consensus sequence RRACH, is a basic surface involving both METTL3 and METTL14 (dark red). Two CCCH motifs N-terminal to the METTL3 MTD also likely contribute to RNA binding.