Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 16, Issue 3, Pages 238-246Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1558
Keywords
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Funding
- European Molecular Biology Organization (EMBO) [240-2005]
- Associazione Italiana per le Ricerca sul Cancro (AIRC)
- Istituto Superiore di Sanita' (ISS)
- American Italian Cancer Foundation (AICF)
- Italian Comitato Interministerial per le Programmazione Economica (CIPE)-2007
- MRC [MC_U117574558, MC_U117533887] Funding Source: UKRI
- Medical Research Council [MC_U117574558, MC_U117533887] Funding Source: researchfish
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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 14-3-3 zeta 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 14-3-3 zeta binding. Using this site, 14-3-3 zeta discriminates between phosphorylated and unphosphorylated KH1, driving the nuclear localization of KSRP. 14-3-3 zeta - 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. (c) 2009 Nature America, Inc. All rights reserved.
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