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Multivalent Interactions with CCR4-NOT and PABPC1 Determine mRNA Repression Efficiency by Tristetraprolin

ABSTRACT: Tristetraprolin family of proteins regulate mRNA stability by binding to specific AU-rich elements in transcripts. This binding promotes the shortening of the mRNA poly(A) tail, or deadenylation, initiating mRNA degradation. The CCR4-NOT complex plays a central role in deadenylation, while the cytoplasmic poly(A)-binding protein PABPC1 typically protects mRNAs from decay. Here, we investigate how tristetraprolin interacts with CCR4-NOT and PABPC1 to control mRNA stability. Using purified proteins and in vitro assays, we find that tristetraprolin engages CCR4-NOT through multiple interaction sites and promotes its activity, emphasizing the importance of multivalent binding for efficient deadenylation. Phosphorylation of tristetraprolin does not affect its interaction with CCR4-NOT or its deadenylation activity, but is essential for tristetraprolin binding to PABPC1. We propose that tristetraprolin promotes the processive deadenylation activity of CCR4-NOT on mRNAs containing AU-rich elements, with phosphorylation-dependent interactions with PABPC1 potentially enhancing deadenylation and promoting regulated mRNA decay.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Eugene Valkov

PROVIDER: MSV000098386 | MassIVE | Mon Jun 30 12:12:00 BST 2025

REPOSITORIES: MassIVE

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