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′UTRs of target mRNAs and subsequently engenders their deadenylation and decay. TTP accomplishes these tasks, at least in part, by recruiting the multi subunit CCR4–NOT deadenylase complex to the mRNA. Here we identify an evolutionarily conserved C-terminal motif in human TTP that directly binds to 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 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.
Highlights
Mammalian gene expression is tightly regulated by an array of post-transcriptional control programs, including mRNA translation and stability
We have identified a novel CCR4–NOT-interaction motif (CIM) at the C-terminus of human TTP
The TTP–CCR4–NOT-Interaction Motif (TTP-CIM) directly binds the CNOT1 subunit of the CCR4–NOT complex. This represents the first structure of the interface between an adenylate uridylate-rich elements (AREs)-BP and the CCR4–NOT complex
Summary
Mammalian gene expression is tightly regulated by an array of post-transcriptional control programs, including mRNA translation and stability. GST-CNOT1800–1015 did not interact with the TTP N-terminal domain in binding assays (Fig. 1C). The TTP binding site is located close to the N-terminus of CNOT1820–999, and is formed by a highly conserved hydrophobic groove between helices α1 and α3 that is flanked by negatively charged patches of amino acids (Fig. 2B).
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