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Mol Cell. 2014 Jun 5;54(5):751-65. doi: 10.1016/j.molcel.2014.03.036. Epub 2014 Apr 24.

Structural and biochemical insights to the role of the CCR4-NOT complex and DDX6 ATPase in microRNA repression.

Author information

  • 1Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
  • 2Max Planck Institute of Biochemistry, Department of Structural Cell Biology, 82152 Martinsried/Munich, Germany.
  • 3Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-109 Warsaw, Poland; Faculty of Biology, University of Warsaw, 02-109 Warsaw, Poland; International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
  • 4Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
  • 5Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-109 Warsaw, Poland; Faculty of Biology, University of Warsaw, 02-109 Warsaw, Poland.
  • 6International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
  • 7Max Planck Institute of Biochemistry, Department of Structural Cell Biology, 82152 Martinsried/Munich, Germany. Electronic address: conti@biochem.mpg.de.
  • 8Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland. Electronic address: witold.filipowicz@fmi.ch.

Abstract

MicroRNAs (miRNAs) control gene expression by regulating mRNA translation and stability. The CCR4-NOT complex is a key effector of miRNA function acting downstream of GW182/TNRC6 proteins. We show that miRNA-mediated repression requires the central region of CNOT1, the scaffold protein of CCR4-NOT. A CNOT1 domain interacts with CNOT9, which in turn interacts with the silencing domain of TNRC6 in a tryptophan motif-dependent manner. These interactions are direct, as shown by the structure of a CNOT9-CNOT1 complex with bound tryptophan. Another domain of CNOT1 with an MIF4G fold recruits the DEAD-box ATPase DDX6, a known translational inhibitor. Structural and biochemical approaches revealed that CNOT1 modulates the conformation of DDX6 and stimulates ATPase activity. Structure-based mutations showed that the CNOT1 MIF4G-DDX6 interaction is important for miRNA-mediated repression. These findings provide insights into the repressive steps downstream of the GW182/TNRC6 proteins and the role of the CCR4-NOT complex in posttranscriptional regulation in general.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24768538
[PubMed - indexed for MEDLINE]
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