Structural and biochemical insights to the role of the CCR4-NOT complex and DDX6 ATPase in microRNA repression.
- Mathys H Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
- Basquin J Max Planck Institute of Biochemistry, Department of Structural Cell Biology, 82152 Martinsried/Munich, Germany.
- Ozgur S Max Planck Institute of Biochemistry, Department of Structural Cell Biology, 82152 Martinsried/Munich, Germany.
- Czarnocki-Cieciura M Institute 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.
- Bonneau F Max Planck Institute of Biochemistry, Department of Structural Cell Biology, 82152 Martinsried/Munich, Germany.
- Aartse A Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
- Dziembowski A Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-109 Warsaw, Poland; Faculty of Biology, University of Warsaw, 02-109 Warsaw, Poland.
- Nowotny M International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
- Conti E Max Planck Institute of Biochemistry, Department of Structural Cell Biology, 82152 Martinsried/Munich, Germany. Electronic address: conti@biochem.mpg.de.
- Filipowicz W Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland. Electronic address: witold.filipowicz@fmi.ch.
- 2014-04-29
Published in:
- Molecular cell. - 2014
Amino Acid Substitution
Binding Sites
Crystallography, X-Ray
DEAD-box RNA Helicases
HEK293 Cells
Humans
MicroRNAs
Models, Molecular
Multiprotein Complexes
Mutagenesis, Site-Directed
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Quaternary
Protein Structure, Secondary
Proto-Oncogene Proteins
RNA Interference
Transcription Factors
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.molcel.2014.03.036
- PMID 24768538
- Persistent URL
- https://sonar.ch/global/documents/232272
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