Tryptophan-Mediated Interactions between Tristetraprolin and the CNOT9 Subunit Are Required for CCR4-NOT Deadenylase Complex Recruitment.

Journal of Molecular Biology
D BulbrookJonathan L E Dean

Abstract

The zinc-finger protein tristetraprolin (TTP) binds to AU-rich elements present in the 3' untranslated regions of transcripts that mainly encode proteins of the inflammatory response. TTP-bound mRNAs are targeted for destruction via recruitment of the eight-subunit deadenylase complex "carbon catabolite repressor protein 4 (CCR4)-negative on TATA-less (NOT)," which catalyzes the removal of mRNA poly-(A) tails, the first obligatory step in mRNA decay. Here we show that a novel interaction between TTP and the CCR4-NOT subunit, CNOT9, is required for recruitment of the deadenylase complex. In addition to CNOT1, CNOT9 is now included in the identified CCR4-NOT subunits shown to interact with TTP. We find that both the N- and C-terminal domains of TTP are involved in an interaction with CNOT9. Through a combination of SPOT peptide array, site-directed mutagenesis, and bio-layer interferometry, we identified several conserved tryptophan residues in TTP that serve as major sites of interaction with two tryptophan-binding pockets of CNOT9, previously found to interact with another modulator GW182. We further demonstrate that these interactions are also required for recruitment of the CCR4-NOT complex and TTP-directed decay of an mRNA c...Continue Reading

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Citations

Mar 17, 2019·International Journal of Molecular Sciences·Ruiqing YuQiong Xu
May 1, 2019·Molecular and Cellular Biology·Wi S LaiPerry J Blackshear
May 2, 2020·Genes & Development·Felix RäschCátia Igreja
May 24, 2019·Frontiers in Genetics·Hiroshi OtsukaToshinobu Fujiwara
Jan 30, 2019·Genes & Development·Csilla KeskenyElisa Izaurralde
Oct 13, 2018·The Biochemical Journal·Lorenzo PavanelloGerlof Sebastiaan Winkler
Feb 26, 2021·Journal of Cardiovascular Translational Research·Ye-Shi ChenKai Yin
Jan 10, 2019·Methods : a Companion to Methods in Enzymology·Wi S LaiPerry J Blackshear

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