Phosphorylation-mediated unfolding of a KH domain regulates KSRP localization via 14-3-3 binding

Irene Díaz-Moreno, David Hollingworth, Thomas A. Frenkiel, Geoff Kelly, Stephen Martin, Steven Howell, MaríaFlor García-Mayoral, Roberto Gherzi, Paola Briata, Andres Ramos

Research output: Contribution to journalArticle

Abstract

The AU-rich element (ARE)-mediated mRNA-degradation activity of the RNA binding K-homology splicing regulator protein (KSRP) is regulated by phosphorylation of a serine within its N-terminal KH domain (KH1). In the cell, phosphorylation promotes the interaction of KSRP and 14-3-3ζ protein and impairs the ability of KSRP to promote the degradation of its RNA targets. Here we examine the molecular details of this mechanism. We report that phosphorylation leads to the unfolding of the structurally atypical and unstable KH1, creating a site for 14-3-3ζ binding. Using this site, 14-3-3ζ discriminates between phosphorylated and unphosphorylated KH1, driving the nuclear localization of KSRP. 14-3-3ζ -KH1 interaction regulates the mRNA-decay activity of KSRP by sequestering the protein in a separate functional pool. This study demonstrates how an mRNA-degradation pathway is connected to extracellular signaling networks through the reversible unfolding of a protein domain.

Original languageEnglish
Pages (from-to)238-246
Number of pages9
JournalNature Structural and Molecular Biology
Volume16
Issue number3
DOIs
Publication statusPublished - Mar 2009

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Díaz-Moreno, I., Hollingworth, D., Frenkiel, T. A., Kelly, G., Martin, S., Howell, S., García-Mayoral, M., Gherzi, R., Briata, P., & Ramos, A. (2009). Phosphorylation-mediated unfolding of a KH domain regulates KSRP localization via 14-3-3 binding. Nature Structural and Molecular Biology, 16(3), 238-246. https://doi.org/10.1038/nsmb.1558