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Nat Struct Mol Biol. 2013 Jun;20(6):735-9. doi: 10.1038/nsmb.2572. Epub 2013 May 5.

Structural basis for the recruitment of the human CCR4-NOT deadenylase complex by tristetraprolin.

Author information

1
Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada. marc.fabian@mcgill.ca

Abstract

Tristetraprolin (TTP) is an RNA-binding protein that controls the inflammatory response by limiting the expression of several proinflammatory cytokines. TTP post-transcriptionally represses gene expression by interacting with AU-rich elements (AREs) in 3' untranslated regions of target mRNAs and subsequently engenders their deadenylation and decay. TTP accomplishes these tasks, at least in part, by recruiting the multisubunit CCR4-NOT deadenylase complex to the mRNA. Here we identify an evolutionarily conserved C-terminal motif in human TTP that directly binds a central domain of CNOT1, a core subunit of the CCR4-NOT complex. A high-resolution crystal structure of the TTP-CNOT1 complex was determined, providing the first structural insight, to our knowledge, into an ARE-binding protein bound to the CCR4-NOT complex. Mutations at the CNOT1-TTP interface impair TTP-mediated deadenylation, demonstrating the significance of this interaction in TTP-mediated gene silencing.

PMID:
23644599
PMCID:
PMC4811204
DOI:
10.1038/nsmb.2572
[Indexed for MEDLINE]
Free PMC Article

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