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miRNA‐mediated gene silencing requires the GW182 proteins, which are characterized by an N‐terminal domain that interacts with Argonaute proteins (AGOs), and a C‐terminal silencing domain (SD). In  Drosophila melanogaster  (Dm) GW182 and a human (Hs) orthologue, TNRC6C, the SD was previously shown to interact with the cytoplasmic poly(A)‐binding protein (PABPC1). Here, we show that two regions of GW182 proteins interact with PABPC1: the first contains a PABP‐interacting motif 2 (PAM2; as shown before for TNRC6C) and the second contains the M2 and C‐terminal sequences in the SD. The latter mediates indirect binding to the PABPC1 N‐terminal domain. In  D. melanogaster  cells, the second binding site dominates; however, in HsTNRC6A–C the PAM2 motif is essential for binding to both Hs and DmPABPC1. Accordingly, a single amino acid substitution in the TNRC6A–C PAM2 motif abolishes the interaction with PABPC1. This mutation also impairs TNRC6s silencing activity. Our findings reveal that despite species‐specific differences in the relative strength of the PABPC1‐binding sites, the interaction between GW182 proteins and PABPC1 is critical for miRNA‐mediated silencing in animal cells.

Two PABPC1‐binding sites in GW182 proteins promote miRNA‐mediated gene silencing