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PMID: 19198587 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature structural & molecular biology ·Vol. 16 ·No. 3 ·2009-03-00 ·Pages 238-46

Díaz-Moreno I, Hollingworth D, Frenkiel TA, Kelly G, Martin S, Howell S, García-Mayoral M, Gherzi R, Briata P, Ramos A

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 14-3-3zeta 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 14-3-3zeta binding. Using this site, 14-3-3zeta discriminates between phosphorylated and unphosphorylated KH1, driving the nuclear localization of KSRP. 14-3-3zeta -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.

MeSH Terms
14-3-3 Proteins/metabolism Amino Acid Sequence Binding Sites Cell Nucleus Circular Dichroism Humans Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data Phosphorylation Protein Binding Protein Folding Protein Structure, Tertiary RNA, Messenger/metabolism RNA-Binding Proteins/chemistry,metabolism Sequence Alignment Trans-Activators/chemistry,metabolism
Chemicals
14-3-3 Proteins KHSRP protein, human RNA, Messenger RNA-Binding Proteins Trans-Activators
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Díaz-Moreno Irene
Molecular Structure Division, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Hollingworth David
Frenkiel Thomas A
Kelly Geoff
Martin Stephen
Howell Steven
García-Mayoral MaríaFlor
Gherzi Roberto
Briata Paola
Ramos Andres
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1558
Published
2009-03-00
Epub
2009-00-08
Pages
238-46
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC2858377
Subset
IM
Grants
Wellcome Trust · 082088 · United Kingdom
Medical Research Council · MC_U117533887 · United Kingdom
Medical Research Council · MC_U117574558 · United Kingdom
Databases
PDB
2OPU
External Links
PubMed source DOI: 10.1038/nsmb.1558 PMC Full Text View journal details
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