title: Phosphorylation-mediated unfolding of a KH domain regulates KSRP localization via 14-3-3 binding.
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.
authors.affiliation: Molecular Structure Division, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Díaz-Moreno
authors.forename: David
authors.initials: D
authors.lastname: Hollingworth
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Frenkiel
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.forename: Stephen
authors.initials: S
authors.lastname: Martin
authors.forename: Steven
authors.initials: S
authors.lastname: Howell
authors.forename: MaríaFlor
authors.initials: M
authors.lastname: García-Mayoral
authors.forename: Roberto
authors.initials: R
authors.lastname: Gherzi
authors.forename: Paola
authors.initials: P
authors.lastname: Briata
authors.forename: Andres
authors.initials: A
authors.lastname: Ramos
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002467:Cell Nucleus; D002942:Circular Dichroism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; C105789:KHSRP protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators