Molecular architecture of LSM14 interactions involved in the assembly of mRNA silencing complexes.

Abstract The LSM domain‐containing protein LSM14/Rap55 plays a role in mRNA decapping, translational repression, and RNA granule (P‐body) assembly. How LSM14 interacts with the mRNA silencing machinery, including the eIF4E‐binding protein 4E‐T and the DEAD‐box helicase DDX6, is poorly understood. Here we report the crystal structure of the LSM domain of LSM14 bound to a highly conserved C‐terminal fragment of 4E‐T. The 4E‐T C‐terminus forms a bi‐partite motif that wraps around the N‐terminal LSM domain of LSM14. We also determined the crystal structure of LSM14 bound to the C‐terminal RecA‐like domain of DDX6. LSM14 binds DDX6 via a unique non‐contiguous motif with distinct directionality as compared to other DDX6‐interacting proteins. Together with mutational and proteomic studies, the LSM14‐DDX6 structure reveals that LSM14 has adopted a divergent mode of binding DDX6 in order to support the formation of mRNA silencing complexes and P‐body assembly.