Article
- The EMBO Journal (2006) 25, 163 - 173
- doi:10.1038/sj.emboj.7600918
Published online: 15 December 2005
Subject Categories:
Molecular basis of RNA recognition by the human alternative splicing factor Fox-1
Sigrid D Auweter1,a, Rudi Fasan2, Luc Reymond3, Jason G Underwood4, Douglas L Black4, Stefan Pitsch3 and Frédéric H-T Allain1
- Institute for Molecular Biology and Biophysics, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
- Institute of Organic Chemistry, University of Zurich, Zurich, Switzerland
- Laboratory of Nucleic Acid Chemistry LCAN-EPFL, Lausanne, Switzerland
- Department of Microbiology, Immunology and Molecular Genetics and Howard Hughes Medical Institute, University of California Los Angeles, CA, USA
Correspondence to:
Frédéric H-T Allain, Institute for Molecular Biology and Biophysics, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland. Tel.: +41 1 633 39 40; Fax: +41 1 633 12 94; E-mail: allain@mol.biol.ethz.ch
aPhD Program for Molecular Life Sciences Zurich, Switzerland
Received 15 August 2005; Accepted 24 November 2005
Abstract
The Fox-1 protein regulates alternative splicing of tissue-specific exons by binding to GCAUG elements. Here, we report the solution structure of the Fox-1 RNA binding domain (RBD) in complex with UGCAUGU. The last three nucleotides, UGU, are recognized in a canonical way by the four-stranded 
-sheet of the RBD. In contrast, the first four nucleotides, UGCA, are bound by two loops of the protein in an unprecedented manner. Nucleotides U1, G2, and C3 are wrapped around a single phenylalanine, while G2 and A4 form a base-pair. This novel RNA binding site is independent from the -sheet binding interface. Surface plasmon resonance analyses were used to quantify the energetic contributions of electrostatic and hydrogen bond interactions to complex formation and support our structural findings. These results demonstrate the unusual molecular mechanism of sequence-specific RNA recognition by Fox-1, which is exceptional in its high affinity for a defined but short sequence element.
Keywords:
- alternative splicing,
- NMR,
- protein–nucleic acid recognition,
- surface plasmon resonance
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