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

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


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Models, Biological
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / chemistry*
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
  • Protein Binding
  • Protein Conformation
  • Receptors, CCR4 / chemistry*
  • Receptors, CCR4 / metabolism
  • Ribonucleases / chemistry*
  • Ribonucleases / metabolism
  • Tristetraprolin / chemistry*
  • Tristetraprolin / metabolism


  • CCR4 protein, human
  • Mutant Proteins
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Receptors, CCR4
  • Tristetraprolin
  • ZFP36 protein, human
  • Ribonucleases
  • mRNA deadenylase

Associated data

  • PDB/4J8S