Structural insights into RNA recognition by the alternate-splicing regulator CUG-binding protein 1.

Publication Type:

Journal Article


Structure, Volume 18, Issue 10, p.1364-77 (2010)


Amino Acid Sequence, Base Sequence, Binding, Competitive, CELF1 Protein, Crystallography, X-Ray, Hydrogen Bonding, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Myotonic Dystrophy, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, RNA, RNA Precursors, RNA Splicing, RNA Stability, RNA-Binding Proteins, Sequence Homology, Amino Acid, Substrate Specificity


<p>CUG-binding protein 1 (CUGBP1) regulates multiple aspects of nuclear and cytoplasmic mRNA processing, with implications for onset of myotonic dystrophy. CUGBP1 harbors three RRM domains and preferentially targets UGU-rich mRNA elements. We describe crystal structures of CUGBP1 RRM1 and tandem RRM1/2 domains bound to RNAs containing tandem UGU(U/G) elements. Both RRM1 in RRM1-RNA and RRM2 in RRM1/2-RNA complexes use similar principles to target UGU(U/G) elements, with recognition mediated by face-to-edge stacking and water-mediated hydrogen-bonding networks. The UG step adopts a left-handed Z-RNA conformation, with the syn guanine recognized through Hoogsteen edge-protein backbone hydrogen-bonding interactions. NMR studies on the RRM1/2-RNA complex establish that both RRM domains target tandem UGUU motifs in solution, whereas filter-binding assays identify a preference for recognition of GU over AU or GC steps. We discuss the implications of CUGBP1-mediated targeting and sequestration of UGU(U/G) elements on pre-mRNA alternative-splicing regulation, translational regulation, and mRNA decay.</p>