期刊
MOLECULAR CELL
卷 54, 期 5, 页码 751-765出版社
CELL PRESS
DOI: 10.1016/j.molcel.2014.03.036
关键词
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资金
- FMI
- Howard Hughes Medical Institute IECS
- European Research Council (ERC)
- Max-Planck Gesellschaft
- EU (ERC)
- EU (Marie Curie Initial Training Network RNPnet)
- Deutsche Forschungsgemeinschaft [SFB646, SFB1035, GRK1721, FOR1680]
- Deutsche Forschungsgemeinschaft (CIPSM)
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.
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