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


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.

SUBMITTER: Fabian MR 

PROVIDER: S-EPMC4811204 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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

Fabian Marc R MR   Frank Filipp F   Rouya Christopher C   Siddiqui Nadeem N   Lai Wi S WS   Karetnikov Alexey A   Blackshear Perry J PJ   Nagar Bhushan B   Sonenberg Nahum N  

Nature structural & molecular biology 20130505 6


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 evolutio  ...[more]

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