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Mol Cell. 2014 Jun 5;54(5):737-50. doi: 10.1016/j.molcel.2014.03.034. Epub 2014 Apr 24.

A DDX6-CNOT1 complex and W-binding pockets in CNOT9 reveal direct links between miRNA target recognition and silencing.

Author information

1
Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
2
Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: oliver.weichenrieder@tuebingen.mpg.de.
3
Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: elisa.izaurralde@tuebingen.mpg.de.

Abstract

CCR4-NOT is a major effector complex in miRNA-mediated gene silencing. It is recruited to miRNA targets through interactions with tryptophan (W)-containing motifs in TNRC6/GW182 proteins and is required for both translational repression and degradation of miRNA targets. Here, we elucidate the structural basis for the repressive activity of CCR4-NOT and its interaction with TNRC6/GW182s. We show that the conserved CNOT9 subunit attaches to a domain of unknown function (DUF3819) in the CNOT1 scaffold. The resulting complex provides binding sites for TNRC6/GW182, and its crystal structure reveals tandem W-binding pockets located in CNOT9. We further show that the CNOT1 MIF4G domain interacts with the C-terminal RecA domain of DDX6, a translational repressor and decapping activator. The crystal structure of this complex demonstrates striking similarity to the eIF4G-eIF4A complex. Together, our data provide the missing physical links in a molecular pathway that connects miRNA target recognition with translational repression, deadenylation, and decapping.

PMID:
24768540
DOI:
10.1016/j.molcel.2014.03.034
[Indexed for MEDLINE]
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